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CLINICAL 



PATHOLOGY OF THE BLOOD 



A TREATISE ON THE GENERAL PRINCIPLES AND 
SPECIAL APPLICATIONS OF HEMATOLOGY. 



BY 



JAMES EWING, A.M., M.D., 

PROFESSOR OF PATHOLOGY IN CORNELL UNIVERSITY MEDICAL COLLEGE, NEW YORK CITY. 



SECOND EDITION, REVISED AND ENLARGED. 



ILLUSTRATED WITH FORTY-THREE ENGRAVINGS, AND EIGHTEEN 
COLORED PLATES DRAWN BY THE AUTHOR. 




LEA BKOTHERS & CO., 

NEW YOKK AND PHILADELPHIA 
1903. 



^Q- 1-/^- 



Trl 






THE LIBRARY OF 


Two Copies Receiveo 

OCT 24 ICCO 

Cop>!ighi tntry 

cuss a^ <>' , 


7 / ^ 


HI 



Entered according to the Act of Congress, in the year 1903, by 

LEA BROTHERS & CO., 
in the Office of the Librarian of Congress. All rights reserved. 



DO RN AN, 



PROFESSOR T. MITCHELL PRUDDEN, M.D., LL.D., 

IN APPRECIATION OF HIS CONSTANT AID, 
FREELY RENDERED TO 

THE AUTHOR 

DURING A TERM OF SERVICE IN THE LABORATORY OF THE 

NEW YORK COLLEGE OF PHYSICIANS AND SURGEONS, 

THIS WORK IS 

GRATEFULLY DEDICATED. 



PREFACE TO SECOND EDITION, 



During the past two years the contributions to the knowledge of 
the blood in both its clinical and its pathological aspects have been 
very numerous^ and, in many instances, of fundamental importance. 
In the present edition of this work the author has endeavored to 
incorporate the results of these recent studies in such form as will be 
found available both for the medical practitioner and for the student 
of hematology. This undertaking has required references in the text 
to about four hundred new articles or monographs, which have 
been added to the bibliographical lists. Among the changes thus 
introduced are considerable additions to the chapter on Technics, 
the serum test for blood, and the subject of crioscopy. The discus- 
sion of the morphology of blood cells has been enlarged and a 
new plate added. Some noteworthy additions to the knowledge of 
leukemia have been included in that chapter. The essential features 
of Ehrlich's theories on immunity have been presented, but the 
proper limits of the volume do not permit full discussion of this 
subject. Four new plates and various other figures have been 
added to the illustrations. 

The author acknowledges with thanks numerous valuable sugges- 
tions of his critics, and in many instances has been able to follow 
these suggestions in the revision. 

J. E. 



PREFACE TO FIRST EDITION. 



The rapid advances iu the knowledge of the pathology of the 
blood and the multitudinous applications of this knowledge in 
clinical diagnosis which the last decade has witnessed have brought 
forth several critical treatises on hematology, and still furnish, as 
the writer believes, abundant reason for the preparation of another 
such work in English. 

Although the clinical bearings of the subject have been partly or 
fully accessible to English readers in some recent text-books, many 
later contributions to the pathology of the blood and blood-forming 
organs have had to be sought elsewhere, often in the original 
articles. This omission the present work endeavors to supply. 

Much "of the theoretical discussion in the volume, abstracts of 
special articles, and reports of cases, have been set in fine print, 
so as not to encumber the main text, which has been constructed 
for the student and general reader. The wants of the laboratory 
worker and special student of hematology have been partly con- 
sidered in the chapter on Technics and Chemistry, and in the 
limited references to pathological anatomy. 

There are probably always some deficiencies in a treatise closely 
relating to clinical medicine when that treatise emanates from a 
pathological laboratory. Yet a comparison of the various extant 
works on the so-called '' clinical '' pathology of the blood has 
convinced the writer that clinical pathology is pathology still, 
and that a wide experience at the autopsy table and in the micro- 
scopic examination of diseased tissues furnishes an absolutely 
essential standpoint from which to view pathological changes in the 
blood. The present volume aims therefore to associate changes in 



viii PREFACE TO FIRST EDITION. 

the blood as closely as possible with lesions in the viscera, without 
which combination the former are very often unintelligible. 

In the preparation of the work all available sources of informa- 
tion have been freely consulted, and the writer has profited espe- 
cially by the labors of Ehrlich, Limbeck, Hayem, Lukjanow, 
Lowit, Grawitz, Stengel, Cabot, and many others. An endeavor 
has been made to discriminate between authorities, and in all 
details of important subjects the author has invariably consulted 
the original sources of information. Works without bibliography 
have been of little value in this task, and the considerable number 
of references involved have therefore been included as a feature of 
the present volume. 

J. E. 



CONTENTS. 



INTRODUCTORY. 

ON THE INTERPRETATION OF ANALYSES OF THE BLOOD. 



PART I. 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



CHAPTER I. 



TECHNICS. 



Qualitative tests for blood 

Volume of red cells and plasma 

Enumeration of blood cells 

Hemoglobin, Iron 

Histological examination of blood 

Specific gravit}" . 

Alkalescence 

Osmotic tension . 

Crioscopy .... 

Bacteriological examination . 

Bibliography 



CHAPTER 11. 



CHEMISTRY OF THE BLOOD. 



Red cells, Leucocytes . 

Serum ..... 

The Whole Blood . 

The Blood Ash 

Urea, Uric Acid, Glucose, Glycogen. 
Acetonemia, Lipacidemia, Cholemia 
Specific gravity .... 
Osmotic tension . . . . 

Alkalescence, Basic Capacity . 
Bibliography .... 



PAGE 

23 
31 
35 
43 
53 
57 
59 
61 
62 
67 



71 

75 
77 
78 
80 
83 
84 
88 
90 
93 



CHAPTER III. 



MORPHOLOGY AND PHYSIOLOGY OF RED CELLS. 

Structure and staining reactions . . . . . . . .96 

Degenerative changes . . . . . . . . . .100 

Numbers, Polycythemia, Oligocvthemia . ' . . . . . .104 

Bibliography . . . ' 120 



CONTENTS. 



CHAPTER IV. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 



Morphology . 

Numbers and proportions 

Degenerative changes . 

Leucocytosis, classification 

Relation to immunity . 

Ehrlich's theories 

Clinical tj^pes of Leucocytosis 

Experimental Leucocytosis 

Bibliography 

Eosinophilia 

Lymphocytosis 

Bibliography 



PAGE 

123 
128 
130 
133 
138 
141 
146 
155 
158 
161 
169 
173 



Erythrocytes 
Leucocytes . 
Blood Plates 
Bibliography 



CHAPTER V. 

DEVELOPMENT OF BLOOD CELLS. 



175 
180 
186 
188 



PART II. 



SPECIAL PATHOLOGY OF THE BLOOD. 

CHAPTER VI. 



CHLOROSIS. 




Etiology 


. 191 


Changes in the Blood . . . . . 


. 193 


Regeneration of Blood 


. 197 


Varieties of Chlorosis, Pseudochlorosis ' . 


. 198 


Bibliography ........ 


. 200 



CHAPTER VII. 



PROGRESSIVE 

Historical .... 
Etiology .... 
Pathological changes in Viscera 
Pathogenesis 
Changes in the Blood 
Resume .... 
Bibliography 



PERNICIOUS ANEMIA. 



202 
204 
212 
215 
216 
222 
224 



CHAPTER VIII. 

LEUKEMIA. 



Historical 
Etiology 



227 
230 





COXTEXTS. 


xi 

PAGE 


Pathological changes in Viscera 


. 


. 234 


Pathogenesis 




. 237 


Changes in the Blood . 




. 239 


Diagnosis of Leukemia . 




. 249 


Bibliography 




. 251 



CHAPTER IX. 



PSEUDOLEUKEMIA. 



Historical ........ 

Anatomical characters ...... 

Relation to Leukemia, Pernicious Anemia, Tuberculosis 
Changes in the Blood ...... 

Bibliography ....... 



254 
255 

258 
262 
266 



CHAPTER X. 



AXE:\nA INFANTUM PSEUDOLEUKEMICA. SPLENECTOMY 



Historical. Etiology 
Pathological changes in Viscera 
Changes in the Blood . 
Significance of v. Jaksch's anemia 
Bibliography 



Splenectomy. 

Effects of Splenectomy in Animals 

Splenectomy in ]\Ian 
BilDliography .... 



268 
269 
269 
270 

272 



273 

274 
276 



PART IIL 



THE ACUTE INFECTIOUS DISEASES. 



INTRODUCTORY SECTION 



THE BLOOD IN FEVER. 



Chemical changes, Resistance of red cells , 
Febrile Hj^dremia . . . . 

Action of Bacteria upon the Blood 
Bibliography . . . . , 



277 
278 
279 
280 



CHAPTER XI. 



PNEUMONIA. DIPHTHERIA. 

Pneumonia. 

Gross changes, Red cells. Leucocytes 
Bacteriology. ...... 



282 
289 



xu 



CONTENTS. 



Diphtheria. 

Red cells, Leucocytes 
Effects of Antitoxin 



PAGE 

. 290 
. 292 



CHAPTER XII. 

EXANTHEMATA. 



Variola 

Vaccinia, Varicella 
Scarlatina . 
Measles 



294 
297 
298 
300 



CHAPTER XIII. 

TYPHOID FEVER. 

Red cells, Leucocytes ......... 

Bacteriology .......... 

Bibliography, on Pneumonia, Diphtheria, Exanthems, and Typhoid Fever 



302 
306 
308 



CHAPTER XIV. 



WIDAL S TEST. 



The reaction, etc. 
Bibliography 



311 
319 



CHAPTER XV. 



MISCELLANEOUS INFECTIOUS DISEASES. 



Septicemia, Pyemia, Osteomyelitis 
Appendicitis, Abscess, Erysipelas . 
Acute Rheumatism, Tonsillitis, Whooping-cough 
Inflammations of Serous Membranes 
Gonorrhea, Yellow Fever .... 
Tj^phus Fever, Influenza .... 

Tetanus, Plague, Malta Fever 
Actinomycosis, Glanders, Anthrax 
Bibliography ...... 



321 
325 
327 
330 
331 
332 
333 
335 
336 



CHAPTER XVI. 



SYPHILIS, TUBERCULOSIS, LEPROSY. 



Syphilis, Grades of Anemia .... 
Effects of Mercury .... 

Congenital Syphilis .... 

Tuberculosis, Grades of Anemia 

Tuberculosis of Meninges, Bones and Joints 
Chemistrj^, Bacteriolog}- 



Leprosy 
Bibliography 



338 
339 
342 

343 

347 
348 

349 
350 



CONTENTS. 



Xlll 



PART IV. 



CONSTITUTIONAL DISEASES. 



CHAPTER XA^II. 



HEMOKRHAGIC DISEASES AND DIATHESIS. 



Purpura Hemorrhagica 

Hemophilia 

Scurvy 

Hemocytolysis 

Methemoglobinemia 

Paroxysmal Hemoglobinuria 

Bibliography 



PAGE 

353 
356 
357 
359 
364 
366 
369 



CHAPTER XVIII. 

MISCELLANEOUS CONSTITUTIONAL DISEASES. 



Diabetes 














. 372 


Obesity 














. 374 


Addison's Disease 














. 375 


Osteomalacia 














. 377 


Rachitis 














. 378 


Myxedema . 














. 380 


Bibliography 














. 382 



CHAPTER XIX. 

NERVOUS AND MENTAL DISEASES. 



Mania, General Paresis, Epilepsy, etc. 
Beriberi ..... 
Chorea, Graves' Disease 
Bibliography .... 



384 
386 
386 

387 



PART V. 



GENERAL DISEASES OF VISCERA, 



CHAPTER XX 



THE HEMOPOIETIC SYSTEM. 



Liver, general considerations, special diseases . 
Esophagus ....... 

Stomach, general considerations, special diseases 
Intestines, absorption and depletion, special diseases 
Bibliography . . . . . 



389 
394 
395 
402 
405 



XIV 



COXTEXTS. 



CHAPTER XXT. 

LUXGS, HEART, KIDNEYS. 



Diseases of Lungs, Asphyxia . 
Diseases of Heart, Malignant Endocarditis 
Diseases of Kidneys, Uremia . 
Bibliography ..... 



CHAPTER XXII. 

MALIGXAXT TUMOKS. 



Carcinoma . 

Sarcoma 

Bibliograph}" 



PAGE 

. 407 
. 410 
. 414 
. 418 



421 
427 
428 



PART VI. 

ANIMAL PARASITES. 

CHAPTER XXIII. 

MALARIA. 



Technics ..... 
Morphology of Parasites 
Plurality of species in Estivo-autumnal group 
Crescents, Flagellate Bodies . 
Development in Mosquito 
Conjugation .... 

Occurrence of Parasites in the Blood 
Malarial Anemia .... 
Leucocytes in Malaria . 
Bibliography .... 



Morphology of Spirillum 
Changes in the Blood 
Bibliograph}' 



CHAPTER XXn\ 



RELAPSING FEVER. 



CHAPTER XXA^ 



MISCELLANEOUS PARASITIC DISEASES. 



431 
435 
446 
450 
453 
454 
455 
459 
462 
464 



466 

468 
469 



Trichina spiralis ....... 






. 470 


Distoma hematobium 






. 472 


Ascaris lumbricoides, Anguillula stercoralis 






. 473 


Ankvlostoma duodenale, Bothriocephalus latus 






. 474 


Filariasis ........ 






. 478 


Trypanosomiasis ....... 






. 480 


Bibliography ....... 






. 481 



Appendix 



483 



LIST OF PLATES. 



PLATE PAGE 

I. Normal blood. Triacid stain 97 

IL Normal blood. Eosin and methylene blue ..... 124 

III. Normal blood. Fixed in alcohol. Stained two hours by the Nocht- 

Komanowskj method 127 

IV. Mild chlorosis. Eosin and methylene blue 194 

V. Severe chlorosis. Eosin and methylene blue 198 

VI. Progressive pernicious anemia. Eosin and methylene blue . .218 

VII. Secondary pernicious anemia. Eosin and methylene blue . . . 220 

VIII. Myelogenous leukemia. Triacid stain 240 

IX. Lymphatic leukemia. Eosin and methylene blue .... 244 

X. Degenerating leucocytes in myelogenous leukemia. Triacid stain . 242 

XL Mast-cells. Ehrlich's dahlia stain 248 

XII. Glycogenic degeneration of leucocytes. Iodine and potassium iodide 

in mucilage of acacia ......... 289 

XIIL Agglutinated red cells ......... 361 

XIV. Developmental cycle of benign tertian parasite . . . . . 436 

XV. Cycle of quartan parasite 443 

XVI. Cycles of estivo-autumnal parasite ... .... 445 

XVII. Flagellating malarial parasites. Cerebral cortex in pernicious malaria 453 

XVIII. Conjugating cycle of tertian malarial parasite ..... 455 



INTRODUCTORY. 



ON THE INTERPRETATION OF ANALYSES OF THE BLOOD. 

Plethora. Although the older physicians regarded the existence 
of a true plethora as an important and well-established fact in path- 
ology, this vieWj lacking proof, received a serious blow from the 
work of Ludwig's pupils, v. Lesser and Worm-Muller, and from 
the authoritative conclusion of Cohnheim. Lesser and Worm- 
Muller, attempting to produce artificial plethora by transfusion of 
blood in animals, found that when the red cells were thereby in- 
creased 28 per cent, the numbers fell to normal on the following 
day, and when increased 58 per cent, the blood became normal on 
the twenty-third day, while the total quantity of blood might be 
doubled without abnormal symptoms, owing to the rapid return to 
the normal quantity. Likewise, Hamburger was unable to produce 
a permanent plethora in horses, by the injection of large quantities 
(7 litres) of 5 per cent, soltition of sodium sulphate, finding that 
the isotonic power of the blood, thus increased, became normal in 
one-half to two hours, while nearly all traces of the salt disappeared 
from the blood in twenty-four hours. Instead of drawing from these 
data the conclusion that continuous plethora cannot be induced 
artificially, the unwarranted claim was advanced that a true plethora 
does not exist (cf. v. Eecklinghausen, Lukjanow). Against this con- 
clusion stood the daily observation of clinicians and pathologists, at 
the bedside and in the dead-house, that there are extreme variations 
in the quantity of blood in the vessels of different subjects, in divers 
states of health and disease. Oertel especially strongly maintained, 
without being able to offer proof, that the volume of blood might be 
reduced in endocarditis and with good therapeutical effect. Positive 
data on the question were gathered by Bergmann and Heissler, pupils 
of Bollinger, and the fact established that there is, in general, a 
direct ratio between the volume of blood and size of the heart, and 
the muscular development of the subject, and an indirect ratio with 
the subject's fat deposits. Though lacking full experimental proof 
it is now generally accepted that the quantity of blood in the body 
is variable, may be increased by hygienic measures, and is diminished 
in many unhygienic and pathological conditions. 

Anhydremia, i. e., a reduction in the volume of blood with concen- 
tration of solids, must be admitted to result from loss of body fluids, 
as by sweating and diarrhea, or by diminished ingestion of water. 

Czerny exposed cats in a warm, dry chamber for thirty-six hours, 
finding that they lost 45 per cent, of their Aveight, the volume of 



1 8 INTB OB UCTOB Y. 

blood was greatly reduced, its viscosity increased, and the red cells 
rose, in one case, to ten millions per cubic millimetre. 

Grawitz found that profuse sweating is followed in the majority 
of cases by a concentration of the blood, in one instance from specific 
gravity 1040 to 1051. A few subjects showed a contrary reaction 
and diminution in gravity (1060 to 1057.5), which Grawitz refers to 
nervous influences. 

Limbeck examined the blood of a case of cirrhosis of the liver 
with extreme ascites, before and after tapping the abdomen. On 
the day after the removal of 18 litres of fluid the red cells had 
risen from 3,280,000 to 5,160,000. Stintzing and Gumprecht have 
made similar observations before and after the removal of large 
serous exudates. 

Grawitz found the specific gravity of the blood at first decreased 
by the intravenous injection of concentrated salt solutions (absorption 
of water), while the administration of the salt by mouth concentrated 
the blood. 

It therefore follows that the ingestion of water and the loss of 
body fluids always produces a more or less transitory effect on the 
volume of the blood. There can be no doubt also that the prolonged 
sweats of phthisis and the severe diarrhea of typhoid fever, dysentery, 
and cholera lead to a more or less continuous reduction in the volume 
of the blood and a concentration of blood cells. 

A very striking illustration of this principle was frequently encountered by 
the writer among the soldiers at Camp Wickoff (1898). When these patients, 
suffering from prolonged malaria with severe anemia, were attacked by typhoid 
fever or acute dysentery, the ordinary watery character of the expressed blood 
drop disappeared, and the blood soon became thick and deep red. 

Herz claims to have recognized an " acute swelling '^ of the red 
cells in febrile conditions, especially in typhoid fever, and v. Lim- 
beck, finding a considerable average increase in the volume of the red 
cells in eight febrile cases, believes that relative oligoplasmia with 
increased volume of red cells is of frequent occurrence in high fevers. 

The effect of nervous influences in altering the quality of the blood 
in the whole or a part of the circulation has been demonstrated by 
numerous studies. 

Cohnstein and Zuntz found that section of the cord above the 
origin of the splanchnic nerves is followed by general dilatation of 
bloodvessels, and reduction in the proportion of red cells. 

Grawitz and Knopfelmacher found, in general, that vasomotor 
paralysis is followed by local and general increase in the volume of 
blood, with diminished specific gravity and proportion of red cells, 
while the opposite effects follow vasomotor constriction of vessels. 

The nervous stimulus of cold baths has been found by Leichten- 
stern, Wick, Knopfelmacher, Winternitz, Thayer, and Grawitz to be 
followed by contraction of vessels and increase in the proportion of 
red and white cells, while the hot pack and the inhalation of amyl 
nitrite have an opposite effect. 

To a similar origin must be attributed the increased gravity of the 
blood observed by Grawitz after the injection of tuberculin, and 



IXTEBPBETATIOX OF ANALYSES OF THE BLOOD. 19 

cultures of the bacillus of cholera and of diphtheria, and the oppo- 
site effect produced by streptococcus and staphylococcus pyogenes and 
B. anthracis. 

The influence of psychical emotions on the character of the blood in 
different regions of the body has been emphasized by Lloyd Jones, 
and is seen especially in the study of the blood in neurotic women, 
Jacobi, examining the blood of an hysterical woman, found on 
IN'ovember 12th 3,892,000 red cells ; on December 11th 8,084,000 
red, 102,200 white cells ; on December 16th 3,393,000 red, 22,000 
white. Grawitz refers to the remarkable increase seen in the specific 
gravity and proportion of cells in the blood of rabbits, in experi- 
ments conducted without anesthesia. The remarkable variations in 
the blood taken from the ears of rabbits, depending on the tempera- 
ture and blood-content of the member, are a matter of common 
observation. 

In the mechanism by which these changes are brought about there 
appear to be many factors. Heidenhain, Lowit, Gartner and Romer, 
find that many substances injected into the blood cause an increased 
flow of lymph. (Extract of cancerous tumors, peptone, tuberculin, 
toxins of B. pyocyaneus and pneumococcus, hemi-albumose, nuclein, 
uric acid, etc.) Heidenhain and Hamburger believe that some sub- 
stances excite a secretory action of the capillary endothelium, whereby 
the fluids of the blood are diminished. 

Grawitz explains the concentration of the blood under the influence 
of cold by the escape of fluids into the tissues, but the experiment of 
Cohnstein and Zuntz offers another explanation, since they found 
under the microscope that capillaries might be so reduced in calibre 
by irritation of vasoconstrictor nerves that no red cells, but only 
plasma, could pass in them. It then appears that many red cells 
may be caught in the contracted capillaries while the plasma passes 
on into the veins. Grawitz concluded from many comparative tests 
that the capillary blood is, in all ordinary conditions, richer in cells 
than that of the veins ; but Becker found no such differences in the 
cells of veins and capillaries, and thinks that the polycythemia of 
cold is referable both to the escape of fluids from the blood and to 
the sifting of cells by the contracted capillaries. It does not appear 
to have been proven that the vascular dilatation produced by heat is 
followed by the return of tissue fluids into the capillaries. It appears 
quite as likely that an irregular distribution of cells and plasma is to 
a larger extent responsible for such local variations in the composition 
of the blood (cf. Winternitz). 

The law that increased blood pressure leads to transudation, 
authoritatively stated by Ludwig and Landois, appears to have a less 
important application here than in more general and more prolonged 
processes. It is not likely that a cold bath can be followed by much 
exudation of serum into the tissues. 

Massage and electricity have been shown, by Mitchell and Cheron, 
to cause an immediate increase in the number of red cells in the 
blood of a part, an effect which may be explained according to the 
above data. 



20 INTB OB UCTOR Y. 

Ekgren found that ten minutes of active massage of body or 
abdomen increased the peripheral leucocytes, chiefly the polynuclears, 
from 1000 to 3000, once 7000. The increase was not marked ten 
minutes after the massage. Oliver was able to lower the red cells 
of the finger 7 per cent, by elevating the arm, while elevation of the 
leg for fifteen minutes lowered the red cells of the toe 14 per cent., 
and raised them in the finger 3 per cent. Exercise and faradism 
caused an increase of 5 to 8 per cent, in the peripheral blood. A 
Turkish bath caused an increase of 15 per cent. 

The importance of the osmotic relations of the blood in controlling 
the volume of red cells and plasma is indicated from the discussion 
in Chapter II. In hydremia and anhydremia Hamburger has shown 
that the isotonic relations of the blood are maintained by a rapid 
interchange of salts and albumins between the cells and plasma, 
with frequent minor changes in their relative volume. From Lim- 
beck's analyses of venous and arterial blood it appears, also, that the 
imbibition of CO2 causes swelling of red cells with absorption of 
water and salts and with relative diminution in the volume of plasma. 



The foregoing considerations are dwelt upon not only because of 
their theoretical interest, but because they deal with fundamental 
facts without the knowledge of which it is impossible to properly 
perform or sensibly interpret the results of an examination of the 
blood. 

To summarize the discussion, it has been shown that there are 
wide variations in the quantity and quality of the blood referable to 
diverse conditions other than disease. 

1. There are considerable physiological variations in the volume 
and composition of the blood, according to the constitution of the 
individual (plethora), and the degree of muscular development. 
Here may be classed the variations between the sexes and between 
different periods of life. Such variations are permanent but usually 
not of extreme grade. 

2. There is a great variety of physiological conditions producing 
marked but transitory changes in the blood, such as active digestion, 
muscular exertion, the ingestion of fluids, profuse perspiration, tem- 
porary cyanosis, etc. 

3. The nervous system has a very striking temporary influence on 
the quality of the blood in local or general areas, acting through the 
cerebral (psychical) or medullary centres, or through local vasomotor 
nerves. 

4. Various local influences may greatly change the quality of the 
blood specimen, as seen in the local and transient effects of cold, 
heat, massage, and electricity. 

5. Many therapeutical procedures may temporarily alter the blood, 
as the aspiration of fluids, administration of diaphoretics, purges, 
vasodilators (amyl nitrite), vasoconstrictors, etc. 



IXTEBPBETATIOX OF ANALYSES OF THE BLOOD. 21 

6. Various pathological conditions may partly or completely 
obscure the real status of the blood, as the sweats of phthisis ; the 
diarrhea of typhoid fever, dysentery, and cholera ; general cyanosis 
or local stasis ; the increased arterial tension of uremia ; the polyuria 
of diabetes and nephritis ; antemortem cardiac failure, etc. 

Having regard to the possible action of any of the above influences, 
one may avoid many of the local disturbances by observing special 
care in the manner of expressing the blood specimen. 

The blood should be expressed by very slight pressure, exerted at 
a distance, from a liberal puncture of the finger-tip or ear-lobe. The 
circulation in the part should be as nearly normal as possible and 
should be uniform, A cold, bloodless tissue is not suitable for fur- 
nishing a blood specimen, and if artificial means are taken to correct 
the condition a sufficient period must elapse to allow the accelerated 
circulation to subside. Blood should be taken not less than four 
hours after a hearty meal, and when comparative tests are made the 
specimens should be taken at the same hour each day. 

The examination having been performed, its results are to he 
interpreted only in the light of the fullest possible clinical information. 
There can be no doubt, as Grawitz has pointed out, that the numer- 
ous contradictory results of hematological studies are largely referable 
to hasty conclusions drawn from figures without regard to the condi- 
tion of the patient or the stage of the disease under consideration. 
Likewise, hematological diagnosis has fallen into much discredit 
from the tendency to offer opinions from the isolated findings of the 
blood test. 



PART I. 
GENERAL PHYSIOLOGY AND PATHOLOGY. 



CHAPTER I 

TECHNICS. 



QUALITATIVE TESTS FOR BLOOD. 

Demonstration of Red Cells. By far the most delicate for blood 
is the demonstration of red cells under the microscope, but as the 
cells are not always preserved in demonstrable form one must 
usually resort to tests for hemoglobin and its derivatives. To 
demonstrate red cells in dry blood stains one should soften the scrap- 

FlG. 1. 




Hemin crystals. (Rieder.) 

ings in some agent which will not lake the corpuscles. Many of the 
fluids recommended for this purpose are active laking agents for 
dried red cells — e. g., 0.8 per cent, salt ; glycerin, 50 per cent.; sodium 
sulphate, 75 per cent. A strong alkaline solution, as KOH 30 per 
cent., is effective in separating the corpuscles and does not dissolve 
them. 



24 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 



The Guaiacum Test. 

To a watery solution of the suspected substance are added a few 
drops of tincture of guaiac, producing a milky precipitate. A few 
drops of hydrogen peroxide added will, in the presence of blood 
pigment, produce a distinct blue color. 

The tincture of guaiac should be freshly made, and diluted to the 
color of pale sherry wine. The guaiac must be added before the per- 
oxide, and the blue color must be developed immediately. Many 
substances turn tincture of guaiac blue, without the presence of per- 
oxide. This test is very delicate, demonstrating one part of fresh 
blood in several thousands of water. It is most effective with fresh 
specimens ; but after two or three years some specimens fail to react 
satisfactorily. Brandenburg finds that leucocytes of myelogenous 
origin, but not the lymphocytes, give this same reaction. The guaiac 
test demonstrates the presence of peroxidases, which exist in most 
animal and vegetable tissues. 

The Hemin Test (Teichmann's). 

A drop of blood or portion of suspected detritus is spread out on 
a glass slide, mixed with one drop of salt solution and dried at a low 
temperature. A cover-glass is then laid over the specimen, filled 
beneath with glacial acetic acid, and the specimen evaporated with 
higher heat, but without boiling. When the fluids have entirely 
evaporated the specimen may be mounted in distilled water and 
examined microscopically for the characteristic crystals of hemin 
(Teichmann's crystals). 

The hemin test, if successful, is absolutely reliable, but often fails, 
in unskilled hands, from (1) alteration of albumins by excessive 
heat, preventing the formation of crystals ; (2) excess of salt solu- 
tion ; (3) violent boiling which drives off free HCl, thus preventing 
the formation of hemin crystals (hydrochloride of hematin). 

Hemin crystals often fail to form from old blood stains in which the 
pigment has become comparatively insoluble from the formation of 
tematin. In such cases a successful result may sometimes be secured 
by allowing the specimen prepared in the usual way with excess of 
dilute acetic or hydrochloric acid to stand overnight (Richter). 

When the stain is very faint or diffuse, or washed, the blood pig- 
ment may be concentrated, as recommended by Wood, by dissolving 
the material in weak alkaline solution, precipitating the pigment 
by boiling after the addition of a few drops of saturated solution of 
sodium tungstate strongly acidified by acetic acid, collecting the 
brownish precipitate, and performing the usual hemin test upon it. 

MEDICO-LEGAL SERUM DIAGNOSIS OF BLOOD. 

One fruitful result of the recent trend of study of the mechanism 
of immunity has been the discovery of a delicate and reliable method 
of distinguishing human blood from that of lower animals. The 



TECHNICS. 25 

first step in the elaboration of this method of serum diagnosis con- 
sisted in the discovery by Tschistowitsch that the serum of an animal 
treated by injections of defibrinated blood or of sernm from another 
species of animal develops the power of agglutinating and dissolving 
the red cells or of causing a precipitate in the serum of the second 
animal. 

This effect was found to be limited to the species of animal whose 
blood was used in the injections, while on the blood of other animals 
the serum remained inert. It soon became apparent that the serum 
of an animal could be made to develop specific powers in relation to 
various animal tissues and albumins and even to vegetable albumins, 
and in 1900 \Yasserman pointed out that the biological method was 
probably capable of separating between all albumins of whatever 
source. 

Almost simultaneously Deutsch, Uhlenhuth, Wasserman and 
Schutze, and Stern applied the method to the identification of blood 
for medico-legal purposes, and showed that it was possible thereby 
to determine the origin of old blood stains. 

Deutsch immunized rabbits by defibrinated human blood and pro- 
duced specific agglutination and solution of the red cells, finding 
that the test could be applied to minute quantities of blood cells 
prepared in the hanging drop. His method is of value in deal- 
ing with small amounts of blood in which the red cells are still 
intact, and, as will be seen, gives reliable information regarding the 
nature of more minute stains than can be treated by the method of 
precipitation of albumins. The other observers employed defibrin- 
ated blood and secured sera which caused precipitates in solutions of 
stains. 

Method of Preparation of the Serum. The rabbit is the animal 
usually employed, and three or four large healthy ones should be 
selected. They should be housed under the best hygienic condi- 
tions. The writer has had very satisfactory results with chickens, 
and there are theoretical reasons for preferring this animal to the 
rabbit. Defibrinated blood squeezed from the fresh placenta or 
drained from the umbilical cord should be used for the injections, 
although less potent sera have been obtained by the use of albuminous 
urine (Stern, Leclainche and Vallee) or of pleuritic exudate (Dinkel- 
spiel, Dieudonne), or of blood from the cadaver (Modica, Ziemke). 
The placental blood may be poured into 100 c.c. Erlenmeyer flasks 
containing broken glass or beads, and defibrination accomplished by 
shaking the flasks for a few minutes. Or the blood may be allowed 
to coagulate and the serum used which separates after forty-eight 
hours. The former method is preferable, as it yields a more hemo- 
lytic antiserum. From six to eight injections of 5 to 10 c.c. each, 
at intervals of three to five days, are required to develop a serum 
of sufficient potency for practical use. 

The intraperitoneal is the preferable route, and the animals usually 
tolerate the injections well. If they lose weight, treatment should 
be suspended for a week. Strict asepsis in the handling of the blood 
and in the injections is, of course, essential. 



26 GENERAL PHYSIOL OGY AND PA THOL G Y. 

The seram may be tested from time to time by drawing a little 
blood from the ear vein, and after a sufficient course of treatment 
the animal may be exsanguinated by exposing the carotid and draw- 
ing the blood through a canula ; but it is well not to sacrifice the 
animal, but to bleed from the marginal ear vein, as a very little sub- 
sequent treatment serves to restore the potency of the serum in an 
animal which has once been bled. 

The drawn blood should be allowed to coagulate, and the serum 
drawn off as clear as possible, centrifuged, if necessary, sealed in 
glass tubes, and kept on ice. Preservation of the active agent may 
be secured by adding a few drops of chloroform, or by evaporating 
the serum on glass plates, the dry residue being dissolved in salt 
solution when needed (Modica and Nobell). 

In testing a suspected stain the material should be dissolved in a 
very little 0.6 per cent, solution of NaCl (c. p.), or in 0.1 per cent. 
NaOH, as preferred by Ziemke, or, if the stain is old and fails to 
dissolve readily, in concentrated potassium cyanide with subsequent 
neutralization with tartaric acid (Ziemke). 

The solution, if turbid, may usually be cleared by the centrifuge 
or by filtration through Schleicher's filter paper (blue ribbon), or 
through an asbestos filter. Small test tubes — diameter 0.5 cm. — are 
required in the work. 

To the filtrate should be added the active serum in proportion not 
greater than 1 : 50. In less dilutions spurious reactions may occur. 

The writer finds it advisable to prepare several controls in each 
test, one of known human blood, and one of the salt or other solu- 
tion used in dissolving the blood stain, one of blood from another 
animal, one of human blood to which normal rabbit serum is added, 
and one of the dissolved stain which shall remain untreated. With- 
out such controls a short experience with the method will convince 
one that errors will not infrequently arise from unknown factors. 
All of these specimens should be placed in the thermostat. 

The reaction is positive when a distinct turbidity appears instantly 
or within a few minutes, and when a flocculent precipitate forms 
within three hours. Less definite reactions, such as uniform turbidity, 
cannot at present be accepted (Ziemke), although sera of moderate 
potency give only turbidity at first and require more than three hours 
for precipitation. It is, therefore, important to secure a serum of 
high potency, while, on the other hand, the very powerful sera are 
more apt to cause turbidity in heterologous bloods (Strube, Lenossier 
and Lemoine). On the other hand, the more powerful sera can be 
safely diluted beyond the point where reactions in heterologous blood 
can occur. 

The reaction does not fail with very old specimens of blood, 
although it becomes less distinct the older the specimen. Ziemke 
obtained a cloudiness in three hours from a blood stain twenty-five 
years old ; from blood mixed with earth three years old ; from 
decomposed blood ; and from human blood highly diluted with six 
other kinds of blood. A solution of iron-rust gave no reaction. 
Uhlenhuth secured positive results with blood of the three months' 



TECHNICS. 27 

decomposed cadaver, and with soapsuds containing washed blood. 
The reaction fails when dry blood has been heated one hour at 130° 
C. (Ferrai). Solutions of blood stains on leather may precipitate 
spontaneously, probably from the presence of tannin. 

The delicacy of the test is very great, a reaction having been 
obtained in solutions of blood too weak to give the absorption 
spectra, and in solutions of 1 of serum to 50,000 of blood (Stern). 

Limitations of the Test. The reaction is not, in one sense, specific, 
and there are only quantitative differences in the results obtained by 
adding humanized sera to various types of blood. However, these 
quantitative differences are very great, and in a large series of 
animals Stern, Wasserman and Schutze, and Nuttall, found none to 
react to humanized sera in any degree comparable to human blood 
except that of the monkey. There are several reports in the litera- 
ture showing that special sera added in slight dilution (1 : 5, 1 : 20) 
cause reactions in the blood of many animals not very closely related, 
but it has been fully shown that if the test serum is diluted up to 
1 : 50 or 1 : 100 and added to blood diluted 1 : 20 or 1 : 100, the results 
become absolutely specific. It is necessary, therefore, to attend care- 
fully both to the dilution of the serum to be tested and to that of 
the active serum used in the tests. Kister and Wolff*, and Strauss 
and the writer have found that most reactions in heterologous bloods 
may be avoided by diluting the test serum 1 : 50. Indeed, most of 
them fail to appear when tlie serum is diluted 1 : 30. 

The writer has compared the reactions of human and monkey 
blood (rhoesus) treated by several potent humanized rabbit sera, and 
finds that the reaction fails in this monkey blood when the test serum 
is diluted 1 : 50. The strength of the solution of the blood to be tested, 
if not greater than 1 : 1000, made comparatively little difference. 

The method is not capable of distinguishing the chemical variety 
of albumin, as Rostocki showed that rabbit serum potent against 
horse globulin precipitated also serum albumin of the horse. 

A more practical difficulty in identifying blood is found in the 
fact that the active serum precipitates albumins from exudates, 
urinary and pleuritic, etc., and from sputum. Strauss and the 
writer secured good precipitates from albuminous diarrheal stools 
not containing blood. It must, therefore, first be determined by 
the hemin test that the stain is blood. Contamination by pus, feces, 
sputum, or urine can usually be detected by appropriate tests. 

Sources of Error. 1. Turbidity or precipitate may occur in any 
blood from too slight dilution of serum. 

2. Potent sera considerably diluted (1 : 20) cause turbidity in 
solutions of blood from closely related animals. 

3. The chemicals used may be impure and cause precipitates. 

4. Chloroform does not inhibit all bacterial growth, and precipi- 
tates occurring after three hours may be referable to this cause. 

5. The reaction of the solution may be too acid or too alkaline, 
and the reaction fails or it occurs in heterologous blood (Ziemke, 
Rostocki). The reaction should be neutral or sliglitly alkaline 
(Lenossier, Lemoine), or slightly acid (Rostocki). 



28 GENERAL PHYSIOL OGY AND PA THOL OGI. 

6. The blood may be mixed with chemicals which cause precipi- 
tates, or human albuminous or mucous exudates may be present in 
the solution and react as blood albumins (cf. Graham-Smith and 

Sanger). 

From the foregoing discussion it is evident that full medico-legal 
reqairements for the positive identification of blood stains may be 
met, under some conditions, by the biological test. These conditions 
are the positive proof by the hemin test that the material is blood 
and the occurrence of a flocculent precipitate appearing within one 
to three hours in the suspected specimen and in no other of the 
several controls when a potent serum is added in proportion of 
1:50 of blood. 

While these conditions can usually be secured when dealing with 
fresh blood in considerable quantities, in the writer's opinion and 
experience the material submitted for medico-legal examination is 
more apt to be old, scanty, and impure, and the difficulty of secur- 
ing a fully satisfactory test by this method is thereby greatly increased. 
With such material one has often to be content with faint turbidities 
instead of flocculent precipitates, and in such cases it would appear, 
as Stoenesco maintains, that a guarded opinion be given and the 
claim made only that the specimen is probably human blood. It 
should be added that an absolutely faultless technique is required, 
and that this can be obtained only after considerable experience. 



SPECTROSCOPIC EXAMINATION OF BLOOD. 

In all cases where a sufficient quantity of dissolved blood can be 
obtained for examination the spectroscopic test is the best means of 
determining not only the presence of blood pigment but also its par- 
ticular form. 

Fig. 2. 





Browning's spectroscope. 



Of fresh blood a 1 per cent, solution yields very distinct absorption 
bands. Recently clotted blood dissolves readily in water. Old 
clots may usually be dissolved by maceration in acetic acid, after 
which the spectrum of acid hematin is obtained. Clots that have 



TECHNICS. 



29 



been exposed to heat must be macerated in ammonia, when the 
spectrum of reduced or of alkaline hematin will result. 

For ordinary clinical work Browning's spectroscope is very satis- 
factory, but absorption bands are more accurately located in larger 
instruments. The small instrument should be supported in a con- 
venient holder in strong daylight or gaslight. By means of a collar 
the width of the aperture may be varied according to the strength 
of the light and opacity of the fluid. By means of the sliding tube 
Fraunhofer's lines are brought into accurate focus. The fluids 
should be examined in small glass vials with flat sides. 

AVhen dealing with fresh blood and unaltered Hb the spectrum is 
that of oxyhemoglobin, which shows two absorption bands between 
D and E, one rather thin and sharp near the orange, and the other 
broader near the green. The indigo and most of the blue is absorbed. 
In strong solutions the two bands of oxyhemoglobin may be united. 



Fig. 3. 



Bed 




0> 


ange 


Yellow 
1 


Green 




^ 


Blue 


Indigo 


A a B C 1 


Eb 


1 


G 










i ' " 








llilllllllliilllllllillilili 


Oxyhcemoglobin 
















1 






















Beduced 
Haemoglobin 




























III 


\ 






ililiilllilllll illlr::.. 


Beduced 
Hoematin 




















iiiii 






1! 




ii 1 




III 


y iill 


r 


Methcemoglobin 
Acid 




























■v,:-! -■■iifMrii:: •, !!' 






i 


Co-Hoemoglobin 




















L 
















Hoematin 
Alkaline 



Spectra of blood pigments. (After Limbeck.) 

If to the solution of oxyhemoglobin is added a little reducing sub- 
stance, such as ammonium sulphide, the color of the fluid becomes 
darker and the spectrum changes, becoming that of reduced hemo- 
globin, giving one broad absorption band between D and E. 

The transformation of the spectrum of oxyhemoglobin to that of 
reduced Hb, by reducing agents, is the positive indication of the 
presence of blood. Cochineal and ammoniated carmine give spectra 
very similar to that of oxyhemoglobin, but on the addition of boric 
acid the spectra of these substances are displaced into the blue, while 
that of blood remains unaffected. The spectra of various other 
vegetable dyes simulate that of blood, but these are bleached by 
sodium bisulphite. 

Hematin is produced by the addition of acids or strong alkalies to 
reduced Hb. In acid solution its spectrum is similar to that of acid 
methemoglobin. In alkaline solution it gives a single rather broad 
band at D. 



30 



GENERAL PHYSIOL OGY AND PA THOL OGY. 



The end-product of the alteration of hemoglobin found in old 
blood stains is iron-free hematoporphyrin^ which must be identified 
by the spectroscope. Kratter and Hammerl claimed to have ob- 
tained the spectrum of this pigment from specimens of incinerated 
blood. To prepare a solution of hematoporphyrin the suspected 
stain should be dissolved in concentrated sulphuric acid, which 
should yield a reddish violet fluid in one-half hour. The spectrum 
of hematoporphyrin resembles that of oxyhemoglobin, but the bands 
are displaced further to the left, especially the small band to the 
left of Z). In alkaline solutions the spectrum resembles that of acid 
he matin (Fig. 4). 













Fig. 4 


















1 

! 






1 


'■M 




















2 

























Spectra of hematoporphyrin. (1) in acid solution, (2) in alkaline solution. 



Clinically, the most important alteration of oxyhemoglobin is that 
into methemoglobin, sometimes detected by the chocolate color of the 
blood. In acid or neutral solution it gives four absorption hands, 
one quite sharp, between C and D ; a second, faint, in the yellow, 
immediately to the right of D ; a third, broad, rather distinct, between 
the yellow and green, and just to the left of E ; a fourth, broad, to 
the left of F, sometimes merged with a complete absorption of the 
blue end of the spectrum. 

The demonstration of carbonic-oxide-Hb is of great clinical im- 
portance in cases of gas poisoning. The blood drop has a rosy 
red tinge, seen alike in both venous and arterial blood. In h per 
cent, dilution a spectrum is obtained which resembles that of oxy- 
hemoglobin, but the bands are broader, and the D band is displaced 
slightly to the right. On the addition of ammonium sulphide the 
spectrum of oxyhemoglobin is replaced by that of reduced Hb, while 
Co-Hb remains unaltered. In applying this test clinically, since 
considerable oxyhemoglobin remains in the blood in most cases, the 
results of spectral analysis are not always clear, and corroborative 
tests are required. 

1. Warm the specimen with equal parts of 10 per cent. ^NaOH ; 
normal blood becomes dark brownish green, the other becomes 
cloudy, then clear red, and red flakes gather on the surface (Hoppe- 
Seyler). 

2. To a 2 per cent, solution of blood add a few drops of orange- 
colored ammonium sulphide containing an excess of sulphur, and 
faintly acidify with a few drops of dilute acetic acid, carefully shak- 
ing. Carbonic oxide blood then shows a beautiful rose-red color, 



TECHNICS. 31 

with a llocciileut precipitate, while normal blood becomes greenish 
or reddish gray. The test may be performed in a porcelain dish, 
adding a drop of blood to the mixed reagents (Katayama). 

Kunkel and \Yelzei employ a solution of zinc chloride, or very 
dilute solution of platinum chloride, which color carbonic oxide 
blood bright red, normal blood black. 

Rubner recommends that the suspected blood be diluted four to 
five times with acetate of lead, when normal blood becomes chocolate, 
carbonic oxide blood red. 

Watery neutral solutions of Co-Hb, boiled, yield a clear red coagu- 
lum, while oxyhemoglobin becomes grayish brown (Hoppe-Seyler). 

Estimation of Total Quantity of Blood. 

The limits of error in the methods of estimating the total quantity 
of blood, suggested by Valentin, Yierordt, Buntzen, and Thibault, 
probably exceed the physiological and pathological variations in the 
bulk of this tissue, and are, therefore, not available for clinical 
purposes. 

Haldane and Smith have determined the total quantity of blood in 
fourteen healthy subjects by a method based on the capacity of the 
blood to absorb COg. In these subjects the total bulk of blood varied 
between 3.34 per cent, and 6.27 per cent, (average 4.88 per cent.) of 
the body weight (one-thirtieth to one-sixteenth). The lowest per- 
centage was obtained in a very fat subject. Most physiologists hold 
that the total blood in healthy animals is about one-thirteenth of the 
body weight. 

ESTIMATION OF THE VOLUME OF RED CELLS AND PLASMA. 

The Hematocrit. The idea that the centrifuge might give valu- 
able clinical information concerning the volume of red cells was 
original with Blix, while his instrument and method have been 
improved principally by Hedin, Gartner, and Daland. Although 
hand centrifuges have been used and recommended, the best results 
are obtained only with the electric centrifuge, which is at present in 
the market at a reasonable figure. 

The improved electric centrifuge consists of an iron-clad motor 
carrying a steel shaft and horizontal armature for urine tubes, which 
may be replaced by the hematocrit. A " speed indicator ^' may also 
be attached, which strikes a bell with every 100 revolutions. The 
instrument is practically noiseless even with a very high speed. A 
rheostat is used to control the current and speed. A speed of 8000 to 
10,000 revolutions may be obtained by a small battery or from the 
street current. The hand centrifuge (Fig. 6) may be employed when 
it is not convenient to use electricity. 

The hematocrit attachment consists of two capillary tubes, grad- 
uated in 100 degrees, which are held in the armature by springs. 

Procedure. With walking patients fresh blood may be used. The 
capillary tubes may be filled automatically by holding the tube 



32 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



Fig. 5. 



horizontally, or with one end slightly depressed, and touching it to 
the rather large drop of blood required. The tube is then imme- 
diately inserted in the armature, as in Fig. 6, the opposite tube hav- 
ing previously been filled with water, and the revolutions are begun 
before the blood coagulates. 

When the patient is at a distance the blood must be diluted, 
preferably in 2.5 per cent, solution potassium bichromate, as recom- 
mended by Daland. The blood should be diluted with equal parts 

of this solution, which may be 
accomplished in the red-cell or 
white-cell pipette of the hemo- 
cytometer. With the red-cell 
pipette the capillary tube is filled 
with blood to the mark 1, then 
a small air bubble is drawn in, 
followed by another tube-length 
of blood. Three or four tube- 
lengths of blood should be secured 
in this way and immediately 
mixed with an equal number of 
tube-lengths of diluent. With 
the white-cell pipette a single 
measure of blood and diluent is 
sufficient. The blood and diluent 
should then be mixed by gentle 
shaking, taking care not to en- 
close air bubbles. When diluted 
blood is used both tubes of the 
hematocrit should be filled with 
blood, which may be done by 
allowing the drops to flow in 
from the point of the pipette. 

The tubes are now revolved at 
a speed of eight to ten thousand 
revolutions per minute, for three 
minutes, after which the volume 
of the red cells has been found 
unalterable. 

The question now arises how 
many red cells are contained in 
one degree of the scale. Daland, working extensively with diluted 
blood, places the number at 99,390, practically 100,000. 

Cabot, in a series of 40 comparative tests, using undiluted blood in 
the hematocrit, found variations between 105,000 and 123,000, with 
an average of 112,000. 

Further observations on this point are required, but at present 
the above figures should be used for diluted and fresh blood respec- 
tively, multiplying the result by two when diluted blood has been used. 
Limitations of the Hematocrit. Since the centrifuge does not 
necessarily require the use of diluting fluids, a serious cause of error 




Improved electric hematocrit, with fender, 
rheostat, and speed indicator. The hematocrit 
attachment replaces the urine tubes seen in the 
revolving armature. 



TECHNICS. 



33 



in the method may be removed by the use of fresh blood. It must 
be admitted, however, that the original volume of the red cells can- 
not always be exactly determined by this method, as in pathological 
conditions the compressibility of the corpuscles is not always uni- 
form. Moreover, in altered conditions of the plasma, it is uncertain 
how much change can be wrought in the natural volume of red cells 




Dalaiid's hematocrit. 



by violent centrifugal force. Some fragile cells are probably always 
destroyed during the centrifugal process. 

When diluting fluids are used the error is doubtless increased by 
alterations in the density and composition of the plasma and in the 
volume of the red cells caused by the action of the fluid. Never- 
theless Daland's claim must be admitted that the volume of the red 

3 



3-4 GESEEAL PHYSIOL G Y AXE PA THOL G Y. 

cells, except in leukemia, is determined by this method with accuracy 
sufficient for clinical purposes. The value of such inforoiation is, 
of course, Quite evident. 

The further claim that the hematocrit may give more accurate 
estimates of the number of red cells than does the hematocytometer 
has not been confirmed. The volume of the red cells differs so 
markedly in both the chlorotic and the pernicious anemias that one 
cannot seriotisly consider the project of replacing the hematocytom- 
eter by the hematocrit. Only in the moderate ^secondary anemias, 
with little change in the size and Hb-content of the cells, can the 
volume of the red corpuscles yield reliable indications of their 
number. In cases of leukemia and of extreme leucocytosis so. many 
leucocytes are entangled with the red cells that even the volume of 
the red cells is not accurately told, much less their number. Each of 
these instruments has its proper field to which it should be restricted, 
and as the hematocrit is not overexact in its immediate object, it is 
unscientific to introduce a second source of error, as is done in 
attempting to, compute the number of red cells from their volume. 

It may be added that the value of the hematocrit in estimating the 
character^ and severity of an anemia has not yet been as fully recog- 
nized by clinicians as it deserves, possibly because more attention has 
been paid to the number of red cells than to their functional capacity. 

The reliability of the centrifuge in determining even the volume 
of the red cells has been denied principally by the brothers Bleibtreu, 
and by Bleibtreti and Wendelstadt. These observers devised another 
method of determining the volume of the red cells, which they claim 
gives more trtistworthy results than are obtained by the hematocrit. 
They employed 0.6 per cent, salt solution to prevent coagulation, and 
allowed the blood to settle slowly. The nitrogen-content of the 
supernatant plasma was then determined by Kjeldahl';? method, and 
from tables which these observers constructed the volume of the 
plasma, and hence that of the red cells, could be determined from the 
quantity of X obtained. 

While the results obtained with the hematocrit by several observers 
indicate that the normal volume of red cells varies between 40 and QQ 
per cent., Bleibtreu's method gave normal variations in cadaveric 
blood between 25.15 and 55.8 per cent. (Bleibtreu, Pfeiffer). v. 
Limbeck obtained very low volumes with Bleibtreu's method (24 to 28 
per cent.), which he refers to the use of highly oxidized blood, in 
which he believes the red cells are reduced in volume. The lengthy 
discussion which has prevailed regarding the above points indicates 
that the volmne of the red cells is subject to a considerable variety 
of changes, the origin and significance of which are little understood. 
It has been shown that in order to prevent X from leaving the red 
cells during sedimentation, the exact isotonic tension of the j^lasma 
must be determined in each instance, and a corresponding solution 
of salt used. The isotonic tension of plasma is rarely so low as 0.6 
per cent. XaCl. 

Moreover, supposing that the red cells remain intact during sedi- 
mentation, the pathological variations in the X-content of the plasma, 



TECHXICS. 



35 



depending on several variable nitrogenous bodies, are too frequent 
and marked to permit of any fixed formula to give the volume of 
the serum from its content of nitrogen. (Bleibtreu's method has 
been sharply criticised by Hamburger, Eyckman, Hedin, Biernacki, 
and others.) 

The following table of results obtained by Biernacki well illus- 
trates the unreliability of comparisons betAveen results obtained by 
different procedures and the general inaccuracy of all indirect methods 
of estimating the number of red cells or percentage of Hb from the 
volume of the cells and the specific gravity : 



■ 


Eed cells. 




Content of 






Case. 1 water. 


1 


Hb. 




Number, 


Volume <fo. 




1. Normal i 77. 18 o/o 


5. 037 mil. 56.3 


105 o/o 


2. Normal .... 






77.50 


5.487 


53.6 


100 


3. Cancer of esophagus . 






79.58 


5.175 


52.7 


80 


■i. Rheumatism . 






79. 02 


3.902 


49.1 


85 


5. Chlorosis. 






80.99 


4.958 


50.0 


70 


6. Phthisis .... 






82.37 


4.672 


40.9 


60 


7. Nephritis. 






82.73 


4.800 


40.0 


70 


8. Tabes .... 






83.09 


4.512 


47.6 


65 


9. Chlorosis 






83.04 


4.250 


35.4 


55 


10. Phthisis .... 






84.59 


1.975 


30.9 


50 


11. Ulcer of stomach . 






85.43 


3.825 


37.1 


45 


12. Chlorosis 






89. 36 


2.456 


20.0 


25 


13. Nephritis 






89.46 


1.184 


13.6 


20 



Grawitz determines the volume of red cells in blood drawn in 
considerable quantities by venesection. The specific gravities of the 
whole blood {D^, of the centrifuged serum {D^^ and of the sedi- 
mented red cells {D^, are first determined, from which the volume 
percentage of red cells (x) may be computed by the following formula : 



100 



:d3-Di) 

(Ds-D,)" 



ESTIMATION OF THE NUMBER OF BLOOD CELLS. 



The Hematocytometer. The instrument now in use for counting 
blood cells is that of Thoma, who combined and improved several 
features of instruments previously devised by Hayem, Gowers, and 
Malassez. This apparatus consists of a mixing pipette and a count- 
ing-chamber. 

{ci\ The pipette is a capillary tube graduated in ten equal divisions, 
surmounted by a bulb of exactly 100 times the capacity of the tube, 
and to which is attached a rubber tube and mouth-piece (Fig. 7). 
When the tube is filled with blood up to the mark 1, and this is 
mixed with a diluting fluid sucked up to the mark 101, a specimen 
of blood is obtained in the dilution of 1 : 100. By filling only 
one-half the tube with blood, up to the mark 0.5, the subsequent 
dilution is in the proportion of 1 : 200. The bulb contains a glass 
ball to facilitate the mixing of the blood. 



36 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



(6) The counting-chamber is constructed so as to secure a layer of 
diluted blood A^ millimetre in depth over a certain square area. 

On a thick glass slide is cemented a thinner glass plate, the cen- 
tral portion of which is cut out. In this central area is cemented a 
circular glass shelf the surface of which is exactly yV millimetre lower 
than the surface of the glass plate. When a drop of diluted blood 
is placed on the shelf and covered with a cover- glass, a layer of fluid 
is secured, which is exactly A^ millimetre deep. Between the edge 
of the shelf and the surrounding plate is a moat into which the blood 
may run, but if the fluid should run over the moat and beneath the 
cover-glass, the latter will be elevated and the resulting layer of fluid 
will be more than y^ millimetre deep. The shelf is accurately ruled, 
as shown in Figs. 8 to 11. 

The entire ruled area is nine square millimetres, but only the cen- 
tral square millimetre is used in counting red cells, the others being 



Fig. 7. 




The Thoma hematocytometer. 

required in counting leucocytes. It will be seen that this central 
square millimetre is subdivided into 400 small squares (16 blocks of 
25 each), so that each small square is -^^q sq. mm. Beginning at 
the lower left-hand corner of this area, it will be seen that every 
fifth square, above and to the right, is subdivided by an extra line, 
which is added merely to assist in counting the squares. The out- 
lying square millimetres are variously ruled. 

The above description applies only to the so-called " Zappert " 
chamber which should always be secured, preferably of Zeiss' manu- 
facture. The older chambers cannot well be used for counting 
leucocytes. 

Diluting Fluids. Of the various diluting fluids, Toisson's Mix- 
ture is to be recommended : 

Sodium sulphate 8.0 grm. 

Sodium chloride 1.0 " 

Glycerin pur 30.0 " 

Aq. dest 160.0 " 

Methyl violet 0.25 " 



TECHNICS. 37 

This fluid keeps well, stains the leucocytes, and is of high specific 
gravity so that the red cells settle from it slowly. 

When counting leucocytes only, one may use with advantage a 
0.6 per cent, solution of sodium chloride tinged with gentian violet 
(about 1 drop of saturated alcoholic solution gentian violet to 50 c.c. 
of salt solution). This fluid, Avhile readily prepared, does not keep 
well, and the red corpuscles settle from it so rapidly that it ought 
not to be used in counting these cells. It permits, however, of the 
identification of eosinophile cells and of certain degenerative changes 
in leucocytes. 

A reliable fluid for diluting and permanently preserving blood is 
found in Hayem's Mixture : 

Hydrarg. bichlor 0.5 grm. 

Sod. sulphat 5.0 " 

Sod. chlor 1.0 " 

Aq. dest 200.0 " 

Directions for Using the Hematocytometer. {a) Filling the 
Pipette. The finger-tip of the patient is cleansed with soap and 
water, dried with alcohol, and freely punctured with a needle or a 
specially prepared acne-lancet. Using very gentle pressure only, a 
compact drop of blood is then expressed and the capillary tube is 
filled to the mark 1 or 0.5. In doing this the pipette must be held 
between the thumb and forefinger and the hand steadied against the 
hand of the patient. In well-constructed pipettes the column of 
blood is easily controlled, and after filling the end of the tube may 
be cleansed of adherent blood. The diluting fluid is then sucked up 
to the mark 101, taking care that no blood runs out of the tube 
when it is immersed in the fluid. The specimen is then thoroughly 
mixed by shaking. 

(6) Filling the Counting-chamber. The counting-chamber 
and cover-glass are thoroughly dried and freed from particles of 
dust. One or two drops of diluted blood are first forced from the 
pipette, and a third drop, the size of which can be learned only by 
experience, is deposited on the central shelf. The cover-glass is then 
immediately adjusted, slipping one corner under the forefinger of the 
left hand and controlling the opposite corner with the second finger 
of the right hand, and lowering the glass slowly so as not to include 
air bubbles. Without raising the fingers, now quickly cover the 
other corners with the forefinger of the right and second finger of 
the left hand, and press the cover-glass firmly into position. If the 
application is successful and no dust particles have intervened, New- 
ton^s color rhigs will appear beneath the cover-glass. The formation 
and permanency of these rings may be facilitated by breathing very 
gently on the specimen before applying the cover-glass. 

The specimen should now be held up to the light and examined 
closely to see that the red cells are evenly distributed. An uneven 
distribution is readily detected by the naked eye. After settling a few 
moments the specimen is ready for counting. 

The rapid and successful adjustment of the cover-glass is the most 
important detail in the process of counting blood cells. The cover-glass 



38 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



must be rapidly adjusted^ because from the moment the drop is placed 
upon the shelf there is a rain of cells upon the ruled area out of a 
layer of fluid which is more than -^-^ mm. deep. 

The specimen must be discarded : 

If Newton^ s rings do not appear. 

If any air hubbies are inclosed. 

If the fluid runs underneath the cover-glass. 

If the shelf is not id ell covered by fluid. 

If on inspection, the cells are found unequally distributed. 



Fig. 8. 



Fig. 9. 



ass 



iiKMivMHiiiinni 



lllllllllllillllilll 



ilililHIIiiillllllllili 

iiHii nil nil nil mini 
iiHiiiiiiiiiiiiiiiiiiii 
iMniiiiiiiiiiiiiiiiwi 



Turck. 
Fig. 10. 



Ilir 

Thoma. Centre part. 
Fig. 11. 




Zappert-Ewing. " Thoma. 

Blood-counting chambers. 

(c) Counting the Red Cells. The specimen proving satisfac- 
torjj the count may begin as soon as the cells have settled. Zeiss, 
D., Leitz, No. 7, Reichert's or Bausch and Lomb, ^, are the lenses 
best suited for this purpose, and a good mechanical stage is necessary 
for accurate work. Locate in the field the lower left-hand block of 
25 small squares, begin at the lower and left square and passing to 
the right count all the cells lying in the first five squares. The fifth 
square will be found subdivided. In each square count all the cells 
lying on the lower and left side lines, leaving to be counted with the 
adjacent squares all the cells lying on the lines above and to the right. 
Proceed in this way until at least four blocks of 25 small squares and 
at least 1000 cells are enumerated. The more squares counted over 
the greater the accuracy, and when slight variations are to be de- 
monstrated the entire square millimetre must be covered. If the 



TECHNICS. 39 

cells now appear to be unevenly distribnted the specimen should be 
discarded and another prepared after thoronghly shaking the pipette. 

{d) CoMPUTATiox. Suppose that 1280 cells are enumerated in 
100 small squares, /. e., in \ of the square millimetre. This number 
multiplied by 4 gives the number lying over one square millimetre. 
But the depth of the fluid is only -^-^ mm., so that we multiply again 
by 10 to get the number of cells in one cubic millimetre of fluid. 
Finally we must multiply by 100 because the blood is diluted in the 
proportion of 1 : 100. 

In short, after counting over 100 small squares the result is 
multiplied bv 4-000 to 2:ive the number of cells per cubic millimetre 
(4 X 10 X 100 == 4000). 

If the capillary tube was originally filled to the mark 0.5, the 
dilution is 1 : 200, and the multiplier 8000, If 400 squares are 
counted over, the multiplier is 1000. 

{e) Sources of Error in the Use of the Hematocytometer. 
1. In Securing the Drop of Blood. When much pressure is employed 
in expressing the drop of blood, tissue fluids are squeezed out with 
the blood and the number of red cells is reduced. Reinert found a 
reduction of 722,000 from this cause, which is especially potent in 
cases of dropsy and of severe anemia. 

"When the finger is cold, the circulation poor, or local stasis is pro- 
duced, as by a ligature, the red cells are increased in number. To 
avoid errors of this class, the circulation in the hand should be as 
active as possible, the finger warm, and the puncture liberal enough 
to permit the flow of blood with little pressure applied at some dis- 
tance froQi the puncture. Unless these conditions can be secured it 
is hardly Avorth while to count the blood cells. 

2. In diluting the blood and in transferring it to the counting -chamber 
there are numerous plainly evident sources of error, such as the 
inaccurate filling of the capillary tube, the entrance of air with the 
blood column, the failure to cleanse the tip of adherent blood, the 
escape of blood into the diluting fluid, the overfilling of the bulb 
with diluting fluid, the inadequate mixture of the blood, the failure 
to discharge one or two drops before applying one to the shelf, the 
use of thin cover-glasses, and, above all, delay and inaccuracy in 
adjusting the cover-glass. A little experience and constant care 
serve to eliminate all these difficulties. 

3. In the Construction and Condition of the Apparatus. The ten- 
dency to favor the Zeiss instruments is still probably well founded, 
although Leitz and Reichert are now making very excellent pipettes 
after Grawitz's model. Aside from inaccuracies in the graduation 
of the pipette and construction and ruling of the counting-chamber, 
which are now reduced to a minimum, some pipettes are still on sale 
which are too short, their calibre is too large, and is narrowed at the 
point so that the tubes cannot be cleaned, they require too much 
blood, and the short arm is so soiall that the mark 101 comes too 
close to the bulb. Accurate work cannot be performed with such 
instruments. The worker is at present advised to insist on having 
Grawitz's pipette made by Zeiss, Leitz, or Reichert. 



40 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 

Many close observers find that their pipettes vary with the tem- 
perature. While accurate information on this point is not at hand 
it is just as well to avoid extremes of temperature in making the 
tests and in cleaning the instrument. It has been suggested that the 
polycythemia of high altitudes is partly referable to variations in the 
hematocytometer due to changes in atmospheric pressure, but this 
suspicion has not been confirmed. 

The condition of the pipette is of prime importance. Absolute 
dryness of the tube and bulb is essential. The collection of minute 
water drops in the tube and bulb is responsible for many of the 
shadow corpuscles sometimes seen in the counting-chamber. 

Every few weeks a pipette should be cleaned out with concentrated 
nitric acid. 

(/) Cleaning the Apparatus. After using the pipette the 
rubber tube may be transferred to the long arm and the remaining 
fluid expelled. The tube should then be cleaned thoroughly with 
water, then with alcohol and ether, or, better, with pure ether. It 
must be thoroughly dried before using again. The counting-chamber 
must be cleaned with water only, as alcohol and ether dissolve the 
cement under the shelf and plate. 

{g) The Limit of Error with the Hematocytometer. 
Lyon, Thoma (and Reinert), counting an average of 1141 cells in 
100 squares with a dilution of 1 : 200, found an average error of 
1.82 per cent, in 24 preparations of the same specimen, and in another 
case, counting an average of 934 cells in 100 squares, 1 : 200 dilution, 
an average variation of 2.71 per cent., in 12 preparations of the same 
specimen (Limbeck). These results in the hands of experts using 
special care indicate that a variation of 150,000 cells (3 per cent.) 
cannot be accepted as of any significance. More accurate data are, 
however, seldom required by the clinician. 

Oliver's Hematocytometer. The Principle. When a candle 
flame is viewed through a flat glass tube containing water a trans- 
verse line of bright light is seen which results from the blending of 
numerous images of the flame. The images are produced by the 
minute longitudinal corrugations in the glass which reflect the light 
in various directions. When diluted blood is placed in the tube the 
fluid is sufflciently opaque to shut out the images until a certain 
dilution is reached, when a bright streak of light becomes rather 
suddenly visible. 

Oliver believes that the appearance of this bright horizontal line 
is a very sensitive indicator of the proportion of red cells in the 
fluid, and by a long series of observations has devised an instru- 
ment for determining the number of red cells in blood according to 
this principle. 

The apparatus consists of a measuring pipette (A) ; a drop- 
per for Hayem's fluid (B) ; a flat glass tube graduated in 120 
degrees (C). 

The Procedure. The capillary pipette is carefully filled with 
blood and washed into the tube by means of Hayem's fluid. A 
proper amount of fluid is then added to the diluted blood, and 



TECHNICS. 



41 



Fig. 12. 



the two are mixed by inverting the tube closed by the thumb, 
care being taken not to remove any dikited blood with the thumb. 
The test should be made in a dark room, the light being fur- 
nished by a Christmas candle 
placed about ten feet from the 
operator. When the blood is 
insufficiently diluted the image 
of the candle is invisible when 
looking through the tube held 
horizontally (Fig. 12, D), but at 
a certain 



dilution the 
appear, and 



begin to appear, and at the 
proper dilution a rather com- 
pact transverse line of light 
becomes visible. The bottom 
of the meniscus is then read off 
on the graduated scale. Each de- 
gree of the scale represents 100,- 
000 red cells, the mark 100 cor- 
responding to 5,000,000 cells, 80 
to 4,000,000, 60 to 3,000,000, etc. 
There are both theoretical and 
practical objections to the use of 
Oliver's instrument. Theoreti- 
cally, the method falls in the un- 
desirable class of indirect methods 
about which there are always a 
large series of unknown disturb- 
ing factors which can only be elim- 
inated by prolonged experience. 




Oliver's hematocytometer. A, measuring pi- 
pette. B, dropper. C, mixing tube graduated 
in percentages. D, mode of observation. 



Baumgarten finds that in addition to the variation in size of the corpuscles 
an important source of error is the coagulation of the serum by the Hayem's 
solution. He found variations of 20 to 30 per cent, from the results obtained by 
Thoma's instrument, and concludes that the method is of no value in clinical 
work. Scannell's report, however, is more favorable. 

Practically the difficulty of determining the exact dilution from 
the appearance of a compact line of light is very great. The method 
cannot be recommended until it has received much wider application 
than it has yet enjoyed. 

The Estimation of Leucocytes. 

The leucocytes may be counted by a method which requires a 
special mixing pipette, yielding a dilution of blood in the proportion 
of 1 : 10, and a diluting fluid (3 per cent, acetic acid, tinged with 
gentian violet) which dissolves the red cells, leaving only the stained 
leucocytes to be counted. The same chamber is used as for counting 
red cells, and the same procedure is followed. All the leucocytes 
in one square millimetre having been counted, the result is multi- 
plied by 100, giving the number of leucocytes per cubic millimetre. 



42 GEXEEAL PH YSIOL OGY A^^D PA THOL G Y. 

The disadvantages early recognized in this method are the expense 
and inconvenience of an extra pipette, and a second diluting fluid, 
the time required in preparing a second specimen, the larger quantity 
of blood required, the difficulty sometimes encountered in distin- 
guishing leucocytes from the detritus of red cells, and the impossi- 
bility of separating and evenly distributing the cohesive leucocytes. 

This method has gradually been replaced to a large extent by the 
practice of counting leucocytes in the same specimen prepared for 
counting the red cells. In 1892 the writer found that he secured 
more uniform results with the latter method, and has since found no 
inducement to return to the former. 

The Counting of Leucocytes in the Same Preparation with 
the Red. This method requires the Zappert Chamber, which was 
originally devised by Elsholz for the estimation of eosinophile cells 
in fresh blood. Yarous modifications of the ruling in this chamber 
have been employed, one of which, made by Leitz. at the writer's 
suggestion, is represented in Fig. 10. 

With this chamber, using a Leitz lens Xo. 7, it is possible to 
count over nine square millimetres, which gives almost as many 
leucocytes as are counted in the other method. When the leucocytes 
are normal or reduced in number, it is necessary to count all there 
are in the available 9 sq. mm., and if the number is very low it is 
advisable to prepare a second specimen in the chamber and count the 
white cells in 18 sq. mm. When the leucocytes are increased, 9 
sq. mm., or in cases of leukemia, 6 sq. mm., will yield a number 
large enough to insure an accurate result. 

In order to make the leucocytes visible the Toisson's fluid or other 
solution should contain enough methyl violet to stain these cells dis- 
tinctly. With a little practice the eye very readily picks out the 
bluish highly refractive leucocytes. 

What has been said regarding the condition of the local circula- 
tion, and the effects of pressure in expressing the blood, is to be 
specially emphasized when estimating the number of leucocytes in a 
specimen of blood. 

Computation. Divide the number of leucocytes counted by the 
number of square millimetres traversed in the count and multiply by 
1000. The result is the number of leucocytes per cubic millimetre 
of blood. 

If the original dilution is 1 : 200, which ought not to be employed 
except in cases of leukemia, the multiplier is 2000. Thus if 54 
leucocytes are counted in 9 sq. mm. (dilution 1 : 100) the number 
per cubic mm. is 6000 (54 -^ 9 X 1000). 

The Enumeration of Eosinophile Leucocytes, (a) In the Same 
Preparation with the Red Cells. When the blood is diluted, 1 : 100, 
with 0.6 per cent, salt solution tinged with gentian violet, the leuco- 
cytes retain their natural size and shape and eosinophile cells can be 
readily identified by their large, greenish, refractive granules. In 
cases of myelogenous leukemia this method is satisfactory, but when 
the eosins are present in their usual numbers (1 to 5 per cent.) one 
must count a larger number than can be found by this method. The 



TECHNICS. 43 

usual expedieut is to estimate their perceutage from a dried specimen 
of blood, and then to calculate their number from the total number 
of all leucocytes counted by other methods. Thus, if the count shows 
12,000 leucocytes per cubic mm. and the dried blood slide shows 2 
per cent, of eosins their number will be 240 per cubic millimetre. 
This method is sufficiently accurate for clinical purposes. 

(6) By Means of Thoma's Special Pipette for the Enumeration of 
Leucocytes. Klein, Mueller and Reider, and Elsholz, have employed 
methods for the accurate estimate of eosinophile cells adapted to 
finer clinical work and to experimental research. They use the large 
pipette of Thoma which gives a dilution of 1 : 10. The capillary tube 
is filled with blood to the mark 1, and the bulb is half filled wdth 
the following solution : watery eosin (2 per cent.), 7 c.c. ; glycerin, 
45 c.c. ; aq. dest., 55 c.c. After shaking three to four minutes the 
bulb is filled to the mark 11 with the following staining fluid : aq. 
dest., 15 c.c. ; gentian violet, cone. aq. sol., 5 drops ; alcohol, 1 drop. 

In specimens thus prepared both neutrophile and eosinophile 
leucocytes are readily distinguished, the eosinophile cells being par- 
ticularly brilliant. The red cells are dissolved and the leucocytes 
concentrated so that a sufficient number of eosinophile cells may be 
counted. 

Zappert's extensive studies of eosinophile leucocytes were conducted 
with specimens diluted in the large pipette of Thoma, by the follow 
ing solution : 1 per cent, osmic acid sol., 5 c.c, to which are added 
5 drops of a filtered mixture — aq. dest., 10 c.c. ; glycerin, 10 c.c. ; 
1 per cent watery eosin, 5 c.c. 



THE ESTIMATION OF HEMOGLOBIN. 

1. Gowers' Hemoglobinometer. This instrument has always 
been largely employed on account of its cheapness and simplicity, 
and the ease and rapidity with which its results are obtained. 
Except with low percentages of Hb, it is tolerably accurate, but 
much less reliable than FleischFs instrument. With low percentages 
of Hb it is well to use a double quantity of blood, halving the result. 

Aside from any inaccuracy in the construction of the apparatus, 
errors arise chiefly from the difficulty of adding exactly the proper 
quantity of water to the blood, and the imperfect comparison of red 
colors in daylight. The apparatus consists of two glass tubes (A, B) 
of exactly equal calibre, one of which is partly filled with gelatin 
colored by picrocarmine so as to represent the color of a 1 per cent, 
solution of normal blood. The second tube carries a graduated scale 
from 10 to 120 and serves to hold the diluted blood. The capillary 
pipette C measures 20 c.mra., the quantity of blood to be used. 

In making the test the pipette is filled to the mark 20 c.mm. with 
blood obtained under the usual precautions. The specimen is quickly 
discharged into the tube B, in which a few drops of distilled water 
have previously been placed. The pipette must then be washed once 
or twice into the tube, the distilled w^ater removing all traces of 



44 



GEXEBAL PHYSIOLOGY AXD PATHOLOGY. 



blood adherent to the inside of the capillary tube. Distilled water is 
now added drop by drop, until the solution of blood, carefully shaken 
and mixed, exactly matches the carmine gelatin. The percentage 
of Hb is indicated by the height of the solution on the scale, reading 
from the middle of the meniscus. The colors match in daylight, and 
the eye may be assisted by holding the tube in front of white paper. 
Haldane's Modification. The picrocarmine solution of Gowers' 
instrument is not stable and has been replaced by Haldane with a 1 
per cent, solution of CO-Hb, which he has foimd to remain unchanged 
for months, even when exposed to heat and sunlight. The specimen 
of blood is drawn as usual and partly diluted. The air in the tube 
is then expelled by a current of illuminating gas introduced from a 

Fig. 13. 




Gowers" hemogrlobiuoineter. 



gas-burner by a rubber tube, and CO-Hb formed by inverting the 
tube, closed by the thumb, several times. The dilution and reading 
are then completed. Haldane claims very accurate results from this 
method. The apparatus with standard solution of CO-Hb is sup- 
plied by the makers of Gowers' hemoglobinometer. 

2. Tallquist's Method of Estimation of Hemoglobin. Tallc|uist 
has recently described a rough method of estimating hemoglobin by 
comparison of a piece of filter paper stained by the blood with a care- 
fully prepared lithographic plate representing the colors of ten solu- 
tions of Hb, ranging from 10 to 100 per cent. A small piece of 
white filter paper of standard quality, such as is sold with the scale, 
is touched to a rather large drop of blood, which is allowed to diffuse 



TECHNICS. 45 

slowly through the paper, so as to give as even a stain as possible. 
Immediately after the stain has lost its lustre and before drying or 
changing color by exposure the percentage of Hb is determined by 
matching with one of the colored areas in the scale. It is unneces- 
sary to mention the serious sources of error in this method, which 
hardly estimates but rather assists one to judge the percentage of Hb. 
3. Fleischl's Hemoglobinometer. (a) Apparatus. This appara- 
tus consists of a metal stand with plate, and plaster mirror (^9) which 
casts diffused light through a circular opening in the plate. Beneath 
the plate, by means of a rack and wheel {T), slides a colored glass 
wedge fixed in a graduated frame (P). The glass wedge and gradu- 
ated scale are arranged so as to indicate the percentage of Hb corre- 
sponding to the different portions of the wedge. In the circular 
opening of the plate fits a cylindrical metallic cell (6r), with glass 

Fig. 14. 




Fleischl's hemoglobinometer. 

bottom and metal partition, one compartment of which lies directly 
over the glass wedge. The other compartment (a) being filled with 
diluted blood, one is able to make a close comparison of the color of 
the dissolved blood with that of the glass wedge. The blood is 
measured by an automatic capillary pipette, while a slowly running 
dropper is provided with which to add distilled water. On the 
handle of each pipette is stamped a number, indicating the cubic 
content of the tube. On the stand of each instrument is also a 
number showing the capacity of the tubes with which it can be used. 
(6) Procedure. One should first see that the automatic pipette is 
in working order, by blowing it out several times with water until 
it fills instantly and completely, after which it must be thoroughly 
dried. A drop of blood having been expressed under very strict 
precautions against pressure, one end of the pipette is lightly touched 



46 GENERAL PHYSIOLOGY AND PATHOLOGY. 

to the drop which instantly fills the tube. There should be neither 
negative nor positive meniscus to the column of blood, but the tube 
should be level full at either end. It should not be immersed in the 
blood drop, otherwise blood will adhere to the sides which cannot 
safely be removed. The tube of blood is immediately transferred 
to one compartment of the cell which has been half filled w^ith dis- 
tilled water, and the blood is thoroughly dissolved by moving the 
tube rapidly from side to side. On withdrawing the tube it should 
be washed into the cell with a few drops of distilled water. With 
the handle of the pipette the blood which collects in the corners of 
the chamber is thoroughly mixed. Both chambers of the cell may 
now be filled level full with w^ater. The thick round cover-glass 
should then be adjusted, avoiding the inclosure of air. Serious error 
may here result by forcing dissolved blood over into the w^ater com- 
partment or over the side of the cell. If the reading is made 
promptly the cover-glass need not be used, but after an exposure of 
ten to fifteen minutes the oxidizing action of the air may darken the 
blood and increase the reading 10 to 15 per cent. 

The reading must be done in a dark room by means of candlelight 
or gaslight. The colors do not match in daylight. The best results 
are obtained by placing the candle about eighteen inches from the 
stand, and by looking through an improvised paper tube which 
exactly fits the cell. With low percentages of Hh a very dim light is 
essential. When the cell is in place, and the light adjusted, the 
wedge is moved with quick rather than gradual turns until the color 
of the glass exactly matches that of the dissolved blood, when the 
percentage of Hb may be read on the scale. Several expedients are 
employed to assist the eye in the comparison of colors. It is well 
to relieve one eye with the other so as not to exhaust the color sense. 
The strength of the light may be varied by altering its distance, but 
the faintest distinct light is usually found to be the best. Two or 
three readings should always be made and the average taken. As 
the graduation of the instrument is more accurate and the matching 
of colors more exact in the middle of the scale, it is advisable to 
use a double quantity of blood when dealing with low percentages 
ofHb. 

(c) Limitations of Fleischl's Instrument. With considerable experi- 
ence and constant care FleischPs instrument yields results which are 
sufficiently accurate for most clinical purposes. One cannot attach 
any significance, however, to a variation of 5 per cent., within which 
figure the ordinary error ought to be limited. 

All the causes of error mentioned as affecting the number of red 
cells may also disturb the percentage of Hb in the blood drop. In 
the procedure the principal difficulties relate to the even filling of the 
tube, the thorough cleaning of the tube, the overflow of blood solu- 
tion into the adjoining chamber, the proper adjustment and regula- 
tion of the light, and the accurate matching of colors. 

The chief sources of error in this method probably lie in the con- 
struction of the instrument. It is a common experience to find that 
different instruments give different results with the same specimen 



TECHNICS. 



47 



of blood, which Limbeck satisfied himself were referable principally 
to differences in the glass wedges. 

The writer tested his own blood with sixteen different instru- 
ments, two of which were old (1892), the others of more recent 
importation (1897). With the two old instruments the Hb regis- 
tered 87 per cent, and 90 per cent. ; with the newer instruments it 
varied between 97 per cent, and 105 per cent., except with one which 
gave 85 per cent, with different cells and different capillary tubes. 
The colored wedge with this instrument was broader and darker 
than usual, and when it was replaced by another wedge the instru- 
ment registered 100 per cent, with the same specimen. The error 
attributable to variations in different tubes and cells the writer finds 
is seldom greater than 5 per cent, among the newer instruments. 
Many old instruments read 10 to 15 per cent, lower than normal. 




Miescher's hemoglobinometer. 



The possible combination of these various defects in construction 
renders it desirable that one should test every new instrument for 
himself, using the blood of five or six healthy subjects. The newer 
instruments w^ill not be found to require much correction. 

Miescher's Modification of Fleischl's Hemoglobinometer. Miescher's 
improvements have removed some important defects in Fleischl's 
instrument, and as it now stands the improved hemoglobinometer 
yields results that leave little to be desired in point of accuracy. 

With this apparatus the blood is diluted by means of a graduated 
pipette very similar to that of Thoma, but yielding dilutions of 
1:200, 1:300, and 1:400, according as the tube is filled with 
blood to the mark i, |, or J. 



48 GENERAL PHYSIOLOGY AND PATHOLOGY. 

Two cells are provided, one with a depth of 15 mm., the other 
with a depth of 12 mm., the percentage of Hb being obtained with 
the deeper cell, and the other being used as a control specimen and 
giving only |- (^|) of the actual percentage of Hb. 

These cells have a projecting partition dividing the compartments, 
along which a grooved cover-glass (D) may be slid, without fear of 
mixing the blood and water. If an excess of the blood solution 
overflows the side of the cell during the adjustment of the cover, no 
harm results, as the blood is already properly diluted in the pipette, 
and the depth in the chamber will always be 15 mm. (or 12). These 
changes add very much to the facility and precision of the method. 

Finally, the cells are covered with diaphragms transmitting a ray 
of light which includes only three degrees on the scale, thus giving 
practically a single color of the wedge for comparison with the blood. 

In the procedure the blood is diluted in the pipette as with the 
hematocytometer, the diluting fluid being distilled water or a filtered 
1 per cent, solution of sodium carbonate. After shaking and clear- 
ing the tube of diluent, one chamber in each cell is filled with diluted 
blood, the opposite chamber with distilled water, and cover-glasses 
and diaphragms are adjusted. Using a small candle and shielding 
the eyes from light, the readings with the two cells are carefully 
taken. The reading with the small cell should be f that with the 
larger. If there is any variation one reading may be used to correct 
the other. For example, suppose the readings to be : 

For the larger chamber (15 mm.) 64 

For the smaller chamber (12 mm.) 50 

If the first reading were absolutely correct the second reading 
should have been 51.2, since 64xf=51.2. Or, assuming the 
second to be correct, the first should have been 62.5, since 
50 X f = 62.5. The mean of 64 and 62.5, i. e., 63.25, should be 
taken as the true value. 

If the original dilution was 1 : 200, the percentage of Hb is 
63.25, the corrected result with the larger cell, but if the dilution 
has been 1 : 300, this result must be multiplied by 1 J, or if 1 : 400, 

The technical difficulties of this method are so slight and the 
results so accurate that the instrument may be recommended over 
any other yet devised for this purpose. 

4. Oliver's Hemoglobinometer. This instrument is constructed 
on the excellent principle of the tintometer, which is extensively 
used in various arts and industries. 

It consists of a series of six red glass disks (a) mounted upon 
white plaster mirrors in convenient frames. These disks represent 
the colors of twelve solutions of blood containing twelve different 
proportions of Hb. Two sets of disks are made, one for reading in 
daylight, the other for candlelight. The latter give more accurate 
results and should be chosen. The intermediate percentages of Hb 
are secured by means of '^ riders ^^ of colored glass to be placed over 
the disks, and which represent respectively 2J and 5 per cent, of Hb 



TECHNICS. 



49 



in the upper half of the scale, but twice that amount in the lower 
half. The disks are graded according to the specific dilution-curve 
of Hb. 



Fig. 16. 




Oliver's hemoglobinometer. a, set of standard colored disks. 5, lancet, c, capillary pipette. 
d, dropper, e, mixing-chamber. 



The blood is measured in an automatic pipette, c, and dilated in a 
cell, e, provided with a white plaster, glass-covered bottom, and 
blue glass cover, which facilitates the reading. The blood is washed 

4 



50 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



from the tube by means of a pipette^ d, with rubber nozzle. The 
tube may be cleaned by means of a thread and needle. 

Procedure. The capillary tube is filled by touching it to the blood 
drop^ and the blood is washed into the cell by attaching the rubber 
nozzle of the pipette^ filled with distilled water, taking care not to 
aspirate any blood into the pipette. The handle of the tube is then 
used to mix the blood, and water is carefully added until the cell is 
level full. The cover is then applied and should inclose a minute 
air bubble, showing that the chamber has not been overfilled. The 
comparison of colors should be made by candlelight, the candle being 
placed at a convenient distance from the disks, and the eye shielded 
by means of a hood or paper tube. Oliver uses a special camera 
with green-glass eye-piece. If the color of the specimen matches 
any one of the disks the reading is completed. If it does not, the 



Fig. 17. 





Dare's hemoglobinometer (x Yz). Parts in position. R, milled Avheel rotating colored disk and 
scale. S, case inclosing disk. T, shield which receives the camera tube U V, visible portion 
of disk backed by white glass. W, white glass back of capillary chamber. Y, candle holder. 
Contents of case : E, colored disk. F, clear glass disk graduated along edge, H. I, white glass 
back. G, opening for pivot. 



disks may be varied by using the ^^ riders,'' adding a clear glass 
disk to the specimen to compensate for the thickness of the 
^^ rider." 

Oliver's instrument presents the advantage of a comparison with 
a single color instead of with a scale of 10 per cent, -f, as in 
Fleischrs. This difficulty is slight, however, and is overcome in 
Miescher's modification of rieischl's instrument. The color of 
FleischPs glass wedge varies according to the specific dilution-curve 
of the colored glass, which differs from the specific dilution-curve 
of Hb. How serious an error may arise with Fleischl's instrument 
from this cause has not been clearly shown. It is probably not 
great, as it is not apparent in the use of Miescher's modification in 
which different parts of the scale are employed. Yet the principle 
of Oliver's instrument is, in this respect, a distinct improvement. 



TECHNICS. 



51 



Fig. 18. 



The technical difficulties are considerably less with Miescher's hemo- 
globinometer. 

5. Dare's Hemoglobinometer. This instrument consists of the 
following parts : 1. A capillary blood chamber com^josed of two 
rectangular pieces of glass which when clamped together leave a thin 
space at one end into which a layer of blood flows by capillary attrac- 
tion. One of the plates is of porcelain glass, which diffuses tlie light. 

This chamber, when filled and adjusted, lies over one of two aper- 
tures which meet the eye glancing through the camera tube of the 
instrument. 

2. The color standard is a semicircular glass plate stained with 
Cassius' golden purple. The plate varies in thickness, giving colors 
which have been accurately adjusted to match various percentages 
of Hb. This plate is inclosed in a rubber case in which it rotates by 
means of a milled screw, carrying with 
it another glass plate with scale adjusted 
from 10° to 120°, which may be read on 
the left of the rubber case. 

3. A detachable camera tube of black 
rubber screws into a movable shield at- 
tached to the case, and when the parts 
are in position this tube furnishes a dark 
chamber through which the operator com- 
pares the color of the blood with that of 
the standard scale, each of which is ex- 
posed by small circular openings in the 
shield. The light is provided by a candle 
fixed to the case. The wick should be 
trimmed low. 

Method of Use. One edge of the capil- 
lary chamber, firmly clamped, is touched 
to a rather large drop of blood sufficient 

to fill it rapidlv and completely, after and damp, j, candle, k, white 
which the chamber is slipped into the ^'^^^ ^ack. l colored disk m, 

ITT 1 .^ 1 , 1 ^ opening through which blood is 

holder, white glass outward. 

Rotating the shield and camera tube 
outward and pointing the instrument to- 
ward a dark background, one finds the 
color scale and blood film clearly outlined 
in the camera tube, and by rotating the milled w^heel the color 
scale is brought to match the blood. The instrument should 
be held steady, so that the flame does not flicker, and the read- 
ing should be completed promptly before the blood coagulates or 
evaporates. 

Dare's instrument is very cleverly devised and constructed. It 
requires the use of pure blood, offers ideal conditions for the com- 
parison of colors, and demands little space in transportation, little 
time in application, and little pains in cleansing, while in accuracy 
of results it stands next, but inferior, in the author's experience, to 
the Miescher-Fleischl apparatus. 




Dare's hemoglobinometer. Hori- 
zontal section. Capillary chamber 



viewed. M', opening in colored 
disk. N, camera tube. O P, clear 
and white glass plates of chamber 
between which lies the layer of 
blood. Q, metallic septum. 



52 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



ESTIMATION OF THE IRON OF THE BLOOD. 

JoUes' Ferrometer. Jolles has devised a method and designed 
apparatus for the estimation of the iron of the blood, which is well 
adapted to clinical purposes. 

The apparatus is manufactured by Keichert, and full directions in 
German accompany each set. 

The procedure is as follows : 

By means of a pipette 0.05 c.c. of blood is transferred to a plati- 
num crucible, and the adherent blood washed out with a few drops 
of water. The blood is then evaporated and incinerated over a 
Bunsen flame. The ash is melted with 0.1 gr. water-free potassium 
bisulphate, until white fumes of sulphuric anhydride cease to rise, 
from the dish. 

Fig. 19. 




Jolles' ferrometer. 



Papers containing the requisite amount of potassium bisulphate 
accompany the instrument. After cooling, the ash is washed into 
cylinder C (Fig. 20) with about 5 c.c. of hot distilled water, which 
is added until the whole quantity is 10 c.c. 

In cylinder O 1 c.c. of the standard solution of iron (0.00005 gr. 
iron oxide with potassium sulphate) is measured by a pipette and 
distilled water added to the mark 10 c.c. Both cylinders are now 
placed in the stand (Fig. 20), and when at even temperature 1 c.c. 
of dilute HCl (33 per cent.) is added to each. 

To cylinder O should then be added 4 c.c. of the solution of 
ammonium sulphocyanide, and to cylinder C about 3.5 c.c, and 
both are shaken after covering the ends with glass plates. 

Cylinder O, containing the blood, is now filled with sulphocyanide 
until it presents a positive meniscus, when it is permanently covered 



TECHNICS. 



53 



Fig. 20. 



and sealed by its glass plate. It may then be placed in the color- 
imeter. In cylinder C the alaminnm float is then adjusted, free 
from air bubbles, and it is also placed in position in the colorimeter. 
The further procedure consists in bringing the color of C to match 
that in C, when yiewed from aboye in the colorimeter. For this 
purpose the fluid in C is allowed 
to run out drop by drop through a 
stopcock until the tw^o colors are 
exactly alike. The comparison 
should be made in daylight. When 
the colors exactly match the height 
of the necessary column of fluid in 
cylinder C may be read off and 
the percentage weight of iron de- 
termined by reference to a table ac- 
companying the instrument. The 
Hb may then be found according 
to y. Jaksch's formula, 



Hb 



100 X m 



0.42 




in which m = the percentage weight 
of metallic iron. 

In order to secure accurate re- 
sults with the f errometer it is neces- 
sary to obserye the same care that 

is required in all quantitatiye chem- joiies' ferrometer. 

ical analyses, especially to ayoid the 

loss of fluids by sputtering from the hot crucible, the use of wet and 
unclean instruments, and the inclosure of air bubbles, etc. Under 
most conditions the Hb may be accurately determined by means of 
the above formula, but from the considerations mentioned under 
" The Occurrence of Iron in the Blood," it will be seen that there 
may be considerable variations between the iron and the Hb-content. 
The ferrometer, therefore, usually gives a higher proportion of Hb 
than does Fleischl's instrument. 



THE HISTOLOGICAL EXAMINATION OF BLOOD. 



The greater part of the examination of blood is conducted with 
dry stained specimens. To prepare such specimens for staining one 
requires only polished glass slides and a Bunsen gas-burner. The 
glass slides must be thoroughly cleaned with soap and water, dried, 
and kept free from dust. Passing them a few times through a flame 
facilitates the even spreading of the cells. 

A rather small compact drop of blood expressed from the finger 
tip under the usual precautions is lightly scraped off with the polished 
edge of one slide and applied to one end of a second slide which 
should lie on firm support. When the blood has spread along the 



54 GEXEBAL PHYSIOLOGY AXD PATHOLOGY. 

edge of the smearer it should be slowly and firmly drawn over the 
surface of the receiving slide. The drop should, if possible, be small 
enough to be exhausted in the smearing, and the thickness of the 
layer can be fully controlled by the degree of pressure. The blood 
should be pushed before the smearer and not trailed after. (See 
Fig. 21.) 

Many prefer to use cover-glasses in spreading the blood. One 
polished cover-glass is touched to the drop of blood and applied to a 
second cover, all corners projecting. When the blood has spread to 
the edges the cover-glasses are gently slid apart without pressure. 
The cover-glasses should be handled with forceps, otherwise the 
moisture of the finger will often crenate many cells. 

The writer prefers to use glass slides, finding that beginners are 
much more successful with the slides than with cover-glasses, that, 
after very little practice, every specimen can be spread successfully ; 
that forceps are not required ; that slides may be handled and trans- 

FlG. 21. 



Method of making blood smears. 

ported without fear of breakage ; that they need not be mounted, 
and, therefore, do not fade like cover-glass specimens, which require 
mounting in balsam ; that they may be restrained if necessary ; and, 
above all, that they may safely ho, fixed in the free flame. 

After spreading, all specimens should be well dried in the air. 
They may then be kept for weeks if wrapped in tissue paper and 
kept from moisture, but it is better to fix them at once. 

Fixation. 1. Heat. In routine work one may discard all other 
methods for that of fixation in the free flame of a Bunsen burner. 
The slide, specimen side up, is passed slowly through the flame until 
it is decidedly too hot for the hand to bear. At this temperature, 
which probably varies between 110° and 150° C, fixation is com- 
plete in one to two minutes. 

A little practice will give the confidence necessary to heat the 
slides hot enough, as one's initial failures from this method almost 
always result from incomplete fixation and subsequent vacuolization 
of the red cells. Overheated slides can usually be seen to change 



TECHNICS. 55 

color in the flame, after which the red cells stain yellowish with eosin. 
The beginner is strongly recommended to perfect himself in this 
simple method of fixation. 

Small ovens provided with a thermometer are made for the fixa- 
tion of blood slides, and may be used when many specimens are in 
hand, or when one does not care to risk the free flame. Specimens 
should be exposed five to ten minutes to a temperature of 
110° to 120° C. 

2. Alcohol. Fixation for ten to thirty minutes in 97 per cent, 
alcohol, or in equal parts of alcohol and ether, is a very reliabe 
method in very general use. Specimens may be left in alcohol for 
twenty-four hours, but do not then stain quite so well. There 
appears to be no advantage in adding ether to the alcohol, which 
even without mixture with the more volatile agent must frequently 
be replaced. Methyl alcohol fixes much more rapidly than ethyl, 
requiring only one to two minutes. It may be advantageously 
employed as a routine fixative, and it is used as a combined fixative 
of blood and solvent of dyes in Jenner's and Goldhorn's stains. 
Fixation in alcohol is to be specially recommended for the malarial 
parasite, but is unsatisfactory when Ehrlich^s triacid stain is to be used. 

3. Fixation by Vapors. Specimens may be fixed by being laid, 
specimen side down, over a wide-mouthed bottle containing 25 per 
cent, formalin, to which the exposure is five minutes, or 2 per cent, 
osmic acid, to which expose two minutes. Both these fluids have to 
be replaced frequently, they considerably alter the staining relations 
of the blood cells, and are inferior to other methods of fixation. 

4. Fixation without Drying. Jolly and others claim that fixation 
after drying destroys many of the essential characters of leucocytes, 
which may be demonstrated in specimens fixed while moist in solu- 
tions of chromic acid. Flemming's stronger solution gave the best 
results in Jolly's hands (1 per cent, chromic acid, 15 parts; 2 per 
cent, osmic acid, 4 parts ; glacial acetic acid, 1 part). Other fixa- 
tives recommended for the same purpose are saturated bichloride in 
0.6 per cent, salt solution (Hermann^s fluid). All these fixatives un- 
doubtedly give better demonstration of nuclear structures and mitotic 
figures than can be obtained after fixation with drying. 

Methods of Staining Dry Blood Specimens. 1. Eosin and 
Methylene Blue. The solutions required are : A saturated alcoholic 
solution of Ehrlich's blood-eosin. A saturated watery solution 
(1 per cent.) of Ehrlich's rectified methylene blue. The latter should 
be at least one week old, as fresh solutions lack selective quality and 
stain the specimen diffusely. After several weeks methylene blue 
in solution diminishes in staining power, while the alcoholic eosin 
absorbs water, and becomes less selective and more powerful. 

In staining flood the specimen with eosin for a few seconds and 
wash in water. If the stain is not effective add more eosin, but the 
water on the slide dilutes the alcohol and renders the second applica- 
tion of eosin much more powerful than the first. Xext flood the 
specimen repeatedly for one minute with methylene blue, wash hastily 
in water, and dry. 



56 GENERAL PHYSIOLOGY AND PATHOLOGY. 

This method may be recommended for all ordinary examinations. 
The blood is stained as shown in Plate II., readily distinguishing 
the various forms of normal leucocytes. It does not stain neutrophile 
granules in leucocytes unless the action of eosin has been prolonged, 
in which case the neutrophile leucocytes can be distinguished from 
the eosinophile only by the size of the granules. Its chief advantage 
is the clear differentiation of basophilic leucocytes and of nuclear 
structures. It clearly demonstrates the malarial parasite, but in 
this field is greatly inferior to Nocht^s method. Its chief disadvan- 
tage is the danger of overstaining with eosin, which prevents the full 
action of methylene blue. 

2. Ehrlich's Triacid Mixture. This fluid has the following com- 
position : 

Saturated watery solution of orange G 120-135 c.c. 

" " " acid fuchsiiie 80-165 " 

" " " methyl green 125 " 

To these add : 

Aqua 300 " 

Absolute alcohol 200 " 

Glycerin 100 " 

The attempt to prepare this mixture is not always successful. 
The smaller quantities of orange G and acid fuchsine are best 
employed, and the solution of methyl green, well seasoned, should 
be added slowly, with stirring, to the mixture of the other dyes. 
The water should be added next, then the alcohol, and, finally, the 
glycerin, with constant stirring. After standing one week the 
mixture is ready for use. Grlibler's preparation of this mixture is 
in the market and is reliable. 

In staining it is only necessary to flood the specimen with the dye 
for one to two minutes, and wash hastily in water. It cannot over- 
stain, but overheated specimens are usually faint, and the red cells 
are yellowish. It stains neutrophile and eosinophile granules deep 
red, the latter being distinguished by their size. It is, therefore, 
indispensable in the diagnosis of leukemia. It is a poor nuclear 
stain, fails to demonstrate the structure of normal mononuclear 
leucocytes, and does not stain the malarial parasite. 

On account of the uniformity of its results many prefer it to eosin 
and methylene blue as a routine method. 

3. Jenner's Stain. Jenner's method of fixing and staining blood 
has now withstood sufiicient trial to warrant its acceptance as one of 
the most important recent methods in blood technics. The speci- 
mens are fixed and stained in the same solution, which is prepared 
as follov/s : equal parts of 1.2 per cent, to 1.25 per cent, of watery 
solution of Grlibler's yellow water-soluble eosin and of 1 per cent, 
watery solution of Griibler's medicinal methylene blue are mixed 
together in an open basin, thoroughly stirred, and allowed to stand 
twenty-four hours. The mixture is then filtered, dried in the air, or 
oven, at 55° C, the filtrate powdered, shaken up with distilled water, 
and washed on a second filter. It is again dried, powdered, and 
stored in bottles for use. The stain is prepared by dissolving 0.5 



TECHNICS. 57 

gramme of the powder in 100 c.c. pure methyl alcohol (Merck's ^^ for 
analytical purposes ''). 

Very thin smears of blood, made on thoroughly clean slides, are 
dried in the air. The dye is poured on the specimen, and staining 
is complete in one to three minutes. The specimens are washed, 
preferably in distilled water, until of a pink color, which usually 
appears in ten seconds. All the cells, their nuclei, and the various 
granules, are well differentiated, Avhile the malarial parasite is densely 
stained and only in the larger parasites does the chromatin fail to 
appear deeply red stained. For this last purpose the method is 
inferior to Xocht's. The powder or fluid dye may be obtained from 
Xew York dealers. 

4. Demonstration of " Mast-cells." The large basophilic granules 
of these cells retain basic dyes with tenacity, and may be demon- 
strated by a mixture of one of these dyes, with a strong decolorizer, 
which removes the stain from most other basophilic structures. 
Ehrlich's dahlia solution is adapted to this purpose : 

Absolute alcohol 50.0 c.c. 

Glacial acetic acid 12.5 " 

Distilled Avater 100.0 " 

Add dahlia to saturation. 

Stain several hours, wash in Avater, decolorize in alcohol or more 
rapidly in 20 per cent. Ac, until the nuclei fade, and wash in water. 
The nuclei of leucocytes are then very pale blue, the mast-cell 
granules very dark blue or black. 

Recent experience has shown that mast-cell granules are very sol- 
uble in water and that their reliable demonstration requires fixation 
and staining by alcoholic solutions. 

Michaelis recommends a solution of thionin or kresyl violet in 50 
per cent, alcohol. The author prefers to use Goldhorn's solution in 
strong methyl alcohol of eosin and polychrome methylene blue. 



ESTIMATION OF THE SPECIFIC GRAVITY OF THE BLOOD. 

Hammerschlag's method is the most practical of the various 
indirect procedures devised for this purpose. A small urinometer 
of suitable dimensions is partly filled with a mixture of chloroform 
(s. g. 1526) and benzine (s. g. 0.889) of a gravity of about 1060. 
By means of a pipette, such as the red-cell mixer of Thoma, a drop 
of blood, expressed with the usual precautions, is transferred to the 
fluid.- In expelling the blood the tip of the pipette should be sub- 
merged and no air should be allowed to pass out with the blood. 
The drop should not be very minute in size and should float on the 
fluid. If it is allowed to sink it will often be lost by spreading out 
on the bottom of the vessel. By adding chloroform or benzine drop 
by drop, as required, and carefully mixing by inverting the urin- 
ometer closed by the palm, a mixture is secured in which the drop 
neither rises nor sinks, but which is of, exactly the same density as 
the blood. The specific gravity of the mixture and of the blood 



58 GENERAL PHYSIOL OGY AND PA THOL OGY. 

may then be taken as with urine. The urinometer should be gradu- 
ated up to 1065, and should be tested in distilled water at 60° F. 
The apparatus should be clean and perfectly dry. The mixture may 
be filtered and used repeatedly. 

Great accuracy can hardly be expected from this method, yet it is 
sufficiently reliable for clinical purposes. Errors arise from changes 
in the blood drop during and after its transfer to the mixture, from 
evaporation, from the escape of gases, from the inclosure or adher- 
ence of minute air bubbles, and perhaps also from the possible 
action of chloroform and benzine upon the blood, which is at present 
an unknown factor. Accordingly, Hammerschlag's method gives a 
uniformly higher gravity than is obtained by more accurate direct 
estimates. Practically, in performing the test one finds that the 
behavior of the drops varies, for reasons which are not clear, some 
rising and others falling in the same mixture. A large drop should 
be secured and followed in the test. 

Since the specific gravity of the blood in simple anemia varies 
principally with the Hb, the percentage of Hb may in many cases 
be calculated with considerable accuracy from the specific gravity. 
Hammerschlag has prepared the following table showing the rela- 
tion of Hb to the specific gravity as determined by his method : 

Specific gravity. Hb. 

1033-1035 25-30 per cent. 

1035-1038 30-35 

1038-1040 35-40 

1040-1045 40-45 

1045-1048 45-55 

1048-1050 55-60 

1050-1053 65-70 

1053-1055 . 70-75 

1055-1057 ..... 75-85 

1057-1060 85-95 

The suggestion that Fleischl's hemoglobinometer be discarded for 
this indirect method of estimating Hb has not found favor. The 
changes in the plasma in severe anemia, leukemia, dropsy, and 
diarrheal diseases, render this practice always unscientific and fre- 
quently very unreliable (cf. Siegel, and Stintzing and Gumprecht). 

Fig. 22. 



Capillary glass tube adapted to various details of blood analysis. 

Schmaltz's Method. A thin-walled capillary glass tube is pre- 
pared, about 12 mm. in length, and of a calibre of about f mm. at 
the ends and IJ mm. at the middle. This is thoroughly cleaned, 
dried, and weighed before and after filling with distilled water. 
After drying with ether the tube is filled with blood and again 
weighed. The weight of the blood divided by that of the water 
gives the specific gravity of the former. 

This is the best of the methods requiring a small quantity of 
blood, and in experienced hands gives more accurate results than 



TECHXICS. 59 

Hammerschlag's method. It is to be especially recommended in 
experimental and laboratory work, but usually requires too much 
blood for its adoption as a routine clinical method, although the 
quantity required, two drops, is not great. The chief sources of 
error are in the difficulty of thoroughly cleaning the tube and inac- 
curacy in the use of the scales. Schmaltz found by controlling his 
results by the use of salt solutions of known density that the error 
did not exceed 0.003 in the coQiputed gravities. 

Comparing the percentage of Hb obtained by Fleischl's method 
with the specific gravity obtained by his own method, Schmaltz con- 
structed the following table : 

Specific gravity. Hb. Specific gravity. Hb. 



1030 .... 20 per cent. ± 1049 

1035 .... 30 " 1051 

1038 .... 35 " 1052 

1041 . . . .40 " 1053.5 

1042.5 .... 45 " 1056 

1045.5 . . . .50 " 1057.5 

1048 . . . .55 " 1059 



60 per cent. 
65 
70 
75 
80 
90 
100 



ESTIMATION OF THE ALKALESCENCE OF THE BLOOD. 

The determination of the alkalescence of the blood is attended 
with very great practical difficulties. This alkalescence being refer- 
able to the presence of carbonates, bicarbonates, and of albumins 
which are retained in solution by acid phosphates, it is always diffi- 
cult to judge of the changes in these principles and the consequent 
variations in reaction produced by the procedures required in alka- 
limetry. If serum alone is titrated, the alkaline principles of the clot 
are left out of account, and if '^ laked " blood is employed there is 
an uncertain factor in the chemical changes produced, especially in 
the delicately balanced albumins and phosphates, during the solu- 
tion of red cells. 

Nevertheless it appears from a considerable number of painstaking 
studies by Landois, v. Jaksch, Kraus, Tausczk, Lowy, Schultz- 
Schultzenstein, Limbeck, and Eigler, that in blood and in serum 
there is a fairly constant group of alkaline principles which may be 
rather accurately measured and which have a distinct and important 
relation to disease (cf. Blood in Fever). 

Four of the many methods employed may be recommended as 
most reliable. 

1. Lowy's Method. In a 50 c.c. flask containing 45 c.c. of 2 
per cent, solution of ammonium oxalate, 5 c.c. or less of fresh blood 
are accurately measured and dissolved. 

Of the solution 5 c.c. are titrated by means of a -^j normal solu- 
tion of tartaric acid, using litmus paper as an indicator. The latter 
may be prepared by soaking prepared paper in an alcoholic solution 
of litmus to which dilute HCl has been added until a violet color 
appears. The end reaction is obtained by adding a drop of blood 
solution to the paper and closely inspecting the color of the outer 



60 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



zone into whicli the fluid diffuses. The result is not affected by 
changes in temperatures. 

Engel's Alkalimeter. Engel has devised an apparatus for the 
clinical estimation of alkalinity according to Lowy's method. A 
large drop of blood is drawn into a special pipette up to the mark 
0.05 and diluted with distilled water to the mark 5.0. After shaking 
the dissolved blood is discharged into a glass cylinder and titrated by 
A^ normal solution of tartaric acid (ac. tartar., 1 gr. ; aq. dest., 1 litre). 
The acid is added drop by drop until a distinct red zone appears, 
when a drop of blood is allowed to diffuse through litmus paper. 
In normal blood about ten drops of acid bring the end reaction. 

Computation. If 0.4 c.c. of acid is required to neutralize 
0.05 c.c. of blood, 8 c.c. of acid will be required to neutralize 1 c.c. 
of blood. One cubic centimetre of ^^ normal tartaric acid neutral- 



FlG. 23. 




Engel's alkalimeter. 



izes 0.533 mg. NaOH (Engel), so that 8 c.c. of acid solution indicate 
the presence in 1 c.c. of blood of 4.264 mg. of XaOH, to which terms 
the alkalinity of the blood is usually reduced. 

2. Method of Schultz-Schultzenstein. By means of the pipette 
of the Fleischl hemoglobinometer, 5 or 7.5 mg. of blood are meas- 
ured, which is dissolved in 12 c.c. of distilled water. This is acidi- 
fied by adding 1.5 c.c. -^^-^ normal H2SO4. After careful mixing a 
drop or two of ethereal solution of erythrosin is added as an indicator 
and the solution titrated, with frequent stirring, by -^^ normal solu- 
tion of KOH. The end reaction is shown by the first appearance 
of a red color in the supernatant ether. The test must be performed 
speedily to avoid obscuring the end reaction by a layer of fibrin pre- 
cipitated by the ether. 

The requirement of a very small quantity of blood renders this 
method specially suitable for clinical purposes. 



TECHNICS. 61 

3. V. Limbeck's Method. To about 200 c.c. of boiled distilled 
water are added 5 c.c. deciuormal HCl solution, and drop by drop, 
with stirring, 5 c.c. of serum spontaneously expressed from a clot. 
The stirring rod should be covered with black gutta-percha. The 
resulting clear and slightly opalescent fluid is now titrated with 
decinormal solution of XaOH. After adding a few drops a precipi- 
tate forms which soon dissolves. The end reaction is reached when 
the abundant precipitate (of albumin) no longer dissolves, which is 
best determined by finding a flocculent precipitate persisting on the 
black rod. 

The same quantity (5 c.c.) of fresh blood may be titrated by this 
method and the total alkalinity of the blood determined. In adding 
blood, however, it must be dropped very carefully into the hot water 
to avoid coagulation. 

The chief technical difficulty with this method lies in detecting 
the end reaction. In case of doubt the precipitate may be dissolved 
by adding 1 to 2 c.c. of acid, as above, and titrating as before. 

There is also the objection that it takes no account of the alkalinity 
referable to albumins. Limbeck doubts, however, if the capacity 
of albumins to neutralize acids ever comes into action in the body, 
and argues that his method estimates exactly, without regard to the 
quantity of albumin, the alkalinity of the salts present in the blood. 

4. Rigler's Method. The blood flows from the vein through a 
canula into two vessels: (1) 3 to 4 c.c. in a tube for centrifuging ; 
(2) a similar quantity into a 50 c.c. flask containing 10 c.c. of 96 
per cent, alcohol. 

The serum is obtained by centrifuging, and is transferred to a 
flask containing 10 c.c. of 96 per cent, alcohol. 

Both flasks are weighed both before and after the addition of blood 
or serum to determine the weight of blood. 

After shaking the specimens stand for half an hour, and then to 
each is added 10 c.c. of neutral distilled water. The alkalinity is 
determined by titration with -^-^ normal HgSO^, using red and blue 
litmus paper as indicators. 

5. Wright has devised and extensively used one of the most 
practical clinical methods of estimating the alkalinity of the blood, 
for the full explanation of which the reader should consult the 
original description. 

Determination of the Coagulability of the Blood. 

Yierordt and Wright have employed methods of determining the 
coagulability of the blood the results from which do not appear to be 
sufficiently accurate even for clinical purposes (Limbeck). 

Estimation of the Osmotic Tension of the Plasma. 

Although comparatively little attention is usually paid to the 
osmotic tension of the plasma, it is evident from the frequent occur- 
rence of hemoglobinemia in various forms of severe anemia, malarial 



62 GEXEEAL PHYSIOL OGY AXD PA THOL G Y. 

and especially liemoglobinuric fever, jaundice, acute poisonings, etc., 
that the condition of the blood in this respect is of prime importance 
in the clinical and pathological study of these diseases. In Ham- 
hurger^s method we possess ready and very exact means of investi- 
gating this problem. 

In a series of test tubes are poured small quantities, accurately meas- 
ured, of the serum to be examined, and to each is added an increas- 
ing quantity of distilled water. The surface of the mixed fluids in 
each tube is then touched with a pipette holding a very little normal 
blood, and the tubes are allowed to stand twelve hours. By that 
time the cells have settled to the bottom in some tubes, while in 
others the supernatant fluid is tinged with dissolved Hb, and one 
notes that tube in which the first traces of Hb appear. Xormal red 
blood cells begin to lose their Hb in solutions of salt containing any 
less than 0.46 per cent, of XaCl. Estimated in terms of XaCl that 
tube of the series which shows the first faint traces of dissolved Hb, 
therefore shows the same osmotic tension as a 0.46 per cent, solution 
of salt. The dilution being known the tension of the original serum 
can be computed as follows : Suppose that to 1 c.c. of serum 0.9 c.c. 
of water added, caused the solution of Hb. Then the tension of the 
original serum is equivalent to 1 — 0.9 X 0.46 = 0.874 per cent, of 
XaCl. 

Hamburger^ points out that all red cells do not dissolve with equal rapidity 
in the same salt solution, and he defines as minimum resistance that strength 
of salt solution in which the weakest cells begin to dissolve, and as maximum 
resistance that solution in which the strongest cells begin to dissolve. In 
order to obtain comparable results he recommends for universal use a series 
of simple tubes in which is secured a dilution of blood in proportion of 1 : 40 
of salt solution. He determines the minimum resistance by adding 0.05 c.c. 
of blood to each of several salt solutions, allows the specimens to stand for 
two hours, and centrifuges in order to determine the first appearance of dis- 
solved Hb. The apparatus with twelve tubes can be obtained from W. J. 
Weller, Kerk Stratt, Utrecht. 



CRIOSCOPY. 

In 1898 Koranyi pointed out that certain iuiportant clinical deduc- 
tions could be drawn from the determination of the freezing point of 
the blood and urine. The method is based upon the fact that the 
presence of elements in solution in a fluid increases the osmotic ten- 
sion of the fluid and lowers its freezing point, both effects following 
invariable physical laws. 

The freezing point of normal blood he found to be 0.56° lower 
than that of water — a fact which is commonly indicated by the 
formula J = 0.56°. A series of clinical studies showed that in 
uncompensated heart disease the lowering of the freezing point of 
the blood, J, is increased, reaching as much as 0.67°, although the 
chlorides of the blood are diminished. This result he shows is owing 
to the retention of CO2 in the system. 

In nephritis J was shown to be much increased, reaching 0.71° in 
a case of uremia. Various characteristic changes were noted in the 



TECHNICS. 63 

blood in anemia and in fevers, where in the absence of cyanosis A was 
less than 0.56°, and in hemoglobinemia, in which J rose to 0.70°. 
Various contributions regarding the clinical value of the test have 
appeared. Koeppe noted variations in healthy subjects between 
0.558° and 0.570°, and in hysteria, aienstruation, gastritis, cancer of 
pylorus, diabetes, nephritis, neurasthenia, pleurisy and pneumonia, 
variations between 0.508° and 0.634°. 

Lindemann finds that in disease of the kidneys the freezing point 
of the serum is unaffected as long as uremic symptoms are absent, 
while in uremia J rises to 0.70°. 

Kummel, in ten cases of nephritis, cystic kidney, and anuria after 
operation, always found J increased to 0.60° to 0.65°, and once to 
0.71°. Ogston reports various conditions in which the value of the 
test appears very uncertain. Ceconi and Micheli could not distin- 
guish by the method the stage of an inflamuiatory exudate, nor 
between exudates and transudates, but found that the freezing point 
of the cerebrospinal fluid was not higher than normal (0.56°), while 
in uremic seizures simulating meningitis J was increased. 

In pneumonia J was always increased to 0.60°, while in typhoid 
fever several observers have demonstrated no change. Carrara finds 
crioscopy of the blood serum the most reliable test for the medico- 
legal diagnosis of death by submersion. The absorption of fresh 
water through the lungs, gastro-intestinal tract, and skin, raises 
the freezing point of blood serum, while salt-water lowers it, in each 
instance more markedly in the left than in the right heart. His 
results were as follows : 

Dog, drowned in fresh water, serum of right heart . . . A = 0.42° 

left heart . . . a = 0.29 

Man, drowned in sea water, serum of right heart . . . A = 1-04 
" " " " " left heart . . . A = 1-18 

In the determination of the freezing point of blood and blood 
serum, Beckmann's apparatus is employed, and preferably the modi- 
fication of Lindemann. 

About 10 c.c. of blood is required, and may be drawn from the 
basilic vein. Coagulation makes no difference in the freezing point 
(Ogston), 

Beckmann's Apparatus. Description of Apparatus (Fig. 24). The 
large vessel (C) for holding the mixture of salt and ice is fitted with a 
perforated iron lid through which passes the handle of a wire stirrer, 
while in the centre is an opening for the tube (B). Another tube (A) 
containing the liquid to be tested, the thermometer (D), and a small 
wire or glass stirrer (E) fits in the mouth of the large tube. 

The thermometer is of peculiar construction, graduated in y^g ° C, 
and permitting very accurate readings over a scale of 10°. It con- 
tains the usual main reservoir at the bulb and also an accessory reser- 
voir at the top of the column (F), by means of which one may add 
to or take from the column of mercury at will. A thermometer with 
^^ fixed zero '^ and without an accessory reservoir may be obtained 
from the makers of Beckmann's apparatus as modified by Linde- 



64 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



Fig. 24. 



mann^ but even with this thermometer the exact freezing point of 
water on the instrument varying from day to day must first be deter- 
mined as described later. Lindemann's ap- 
paratus has the advantage of requiring not 
more than 5 c.c. of serum. 

Application of the Test. The large jar is 
half filled with finely crushed ice and salt. 
The thermometer must first be ^^set'^ so 
that the top of the column of mercury at 
freezing point falls about the middle of the 
graduated scale. This may be done by im- 
mersing the bulb in warm water until the 
mercury in the column joins that in the 
accessory reservoir. Then fill the inner 
tube with distilled water and cool to about 
10° C, immersing an ordinary thermometer 
in the water. Now place the thermometer 
of the instrument in the cool water, and 
when it is thoroughly cool break the column 
of mercury in the reservoir by tapping it 
sharply with the finger. 

The distilled water is now frozen with 
the thermometer immersed, and the exact 
point to which the broken column of the 
mercury falls is taken as the zero of the 
instrument. It will be found that the 
moment that the water congeals the mer- 
cury falls slightly below the true freezing 
point, shortly to rise and remain steady at 
the exact point. 

With Lindemann's thermometer the 
breakage of the column is not required, 
but the exact freezing point of water on 
the thermometer must be determined. 
Having determined the zero of the instru- 
ment, the blood or serum to be tested is 
placed in the inner tube, cooled to near the 
freezing point, and the thermometer im- 
mersed in it. As the fluid cools it must be 
stirred by the glass stirrer. When the fluid congeals the mercury drops 
a fraction of a degree, but soon rises and becomes stationary at the 
freezing point of the fluid. The difference between the freezing point 
of water and that of the fluid, J, may then be determined by the read- 
ing, which should be made as soon as the column becomes stationary. 




Beckmann's apparatus. 



Bremer's Specific Reaction of Diabetic Blood. 

Saturated watery solutions of eosin (watery ?) and of methylene 
blue are mixed in about equal proportions so that a neutral reaction 
is obtained, and the mixture produces little or no stain on litmus 



TECHNICS. 65 

paper. A precipitate formSj soluble in alcohol, insoluble in water, 
Avhicli is filtered, washed, dried, and powdered. To twenty-four 
parts of this powder are added six of powdered methylene blue and 
one of eosin Of this mixed reddish brown powder 0.025 to 0.05 
grm. are dissolved in 10 c.c. of 33 per cent, alcohol, in which solu- 
tion the specimen is stained for four minutes. 

The specimens are prepared by smearing the blood on glass slides 
or covers, and fixed by boiling in equal parts of alcohol and ether 
for four minutes. This may be accomplished by placing the bottle 
of alcohol and ether in hot water at 60° C. 

After washing the stained specimens in water, diabetic blood has 
a greenish tint, while normal blood is reddish violet, and on micro- 
scopic examination the erythrocytes of diabetic blood are found to 
be greenish, while those of normal blood are red. 

Bremer found the reaction in 50 out of 51 cases of diabetes. The 
negative result was obtained in a well-established case, a boy of six- 
teen, in whom glycosuria began after an electric shock. He found 
that the reaction persisted in the absence of glycosuria ; that normal 
blood floated on diabetic urine for fifteen minutes gave the reaction ; 
that blood treated with solutions of glucose failed to give the reac- 
tion ; that the blood in glycosuria artificially produced in animals by 
phloroglucin gave the reaction, while in that produced by phloridzin 
it did not. 

The nature of the reaction is not understood. While some 
observers have convinced themselves that the presence of glucose is 
not sufficient to bring about the altered staining qualities of the 
blood, Hartwig concluded that the glucose first causes a change in 
the Hb which shows itself in the altered reaction of the red cells to 
aniline dyes. Other reducing agents besides glucose are probably of 
importance in this relation (R. Muller). Some have attempted to 
explain the reaction by reference to the changes in alkalescence of 
the blood. Hartwig found the reaction to disappear after the addi- 
tion of alkali to the blood. Although Lowy found a pronounced 
reaction in cases with relatively high alkalescence, Schneider and 
others have shown that the reaction runs parallel with the quantity 
of abnormal acids in the blood. 

Various modifications of the above most approved method have 
been employed successfully by Bremer and others. One of these, 
employed by Bremer, is as follows : 1 per cent, solutions of Congo 
red or of methylene blue stain diabetic blood very slightly, while :1 
per cent, solution of Biebrich scarlet stains it intensely. A directly 
opposite relation holds with normal blood. Eather thick smears of 
blood should be used with this procedure, and the colors compared 
by the naked eye. 

The value of Breuier's test has been confirmed by Le Goff, Eichner 
and Folkel, Lepine and Lyonnet, James, Jeanselme, Badger, and 
Hartwig, but similar reactions have been found in normal blood in 
leukemia, Hodgkin's disease, exophthalmic goitre, and multiple 
neuritis. A partial reaction has been obtained in cachectic condi- 
tions, and Bremer failed to find it in a case of glycosuria of neurotic 

5 



I 



QQ GENEBAL PHYSIOLOGY AND PATHOLOGY. 

origin. Yet in most conditions, other than diabetes, the reaction has 
been found, when present, to be inconstant, and to occur in a very 
small proportion of cases (Lepine, Eichner, Hartwig). 

The technical difficulties in carrying out the test are considerable, 
while a slight variation in technique appears to vitiate the result, 
as is indicated by the failures reported by Patella and Mori, after 
both Bremer's and Williamson's methods. 

Williamson finds that diabetic blood decolorizes solutions of 
methylene blue, while normal blood does not. His test is performed 
as follows : 20 c.mm. (2 drops) of blood are dissolved in 40 c.mm. of 
water, and to the solution is added 1 c.c. of methylene blue (1 : 6000 
solution) and 40 c.mm. of liquor potassce (s. g. 1.058). The vessel 
is then placed in boiling water for four minutes ; diabetic blood 



Fig. 25. 




Pronounced lipemia. Specimen treated with osmic acid. Lower half shows extracellular 
fat globules, upper half having been cleared by oil of turpentine. (Gumprecht.) 

decolorizes the solution, normal blood leaves it deep blue. Diabetic 
urine has the same effect. 

Williamson found this reaction in 6 diabetics and failed to find it 
in 160 cases of other diseases, including one of leukemia. 

Demonstration of Glycogen in Blood. 

Gabritschewsky's method may be employed. The blood smears, 
thoroughly dried in the air, are stained for several minutes in : iodum 
pur., 1 ; KI, 3 ; aq., 100 ; acacia pulv. in excess. 

The presence of glycogen is indicated by the appearance of 
mahogany-brown granules of variable size, in leucocytes and plasma. 
(See Plate XII.) 



TECHXICS. 67 

Czerny claimed that this method demonstrates the presence in the 
blood not of glycogen but of a carbohydrate more nearly related to 
amyloid. Happert^s later studies on the blood of animals support 
the belief that the substance thus demonstrated is really glycogen. 

It is probable that many colorless globules visible in leucocytes 
treated by ordinary staining methods are referable to the former 
presence of glycogen, which is soluble in water and of which the 
reactions are largely destroyed by heat. 

Demonstration of Fat in the Blood. 

The blood smear is fixed in 1 per cent, osmic acid for twenty-four 
hours and counterstained with eosin. The fat particles are then 
stained black. Since all that blackens under osmic acid is not fat, 
a control preparation should be fixed twenty -four hours in alcohol 
and ether, then in 1 per cent, osmic acid for twenty -four hours, 
counterstained with eosin, and the extraction of the fat by ether 
demonstrated by the absence of black particles in cells and plasma. 



BACTERIOLOGICAL EXAMINATION OF BLOOD. 

Apparatus. Any aspirating syringe of the capacity of 10 c.c. which 
can be thoroughly sterilized may be used for drawing the blood, but 
the difficulty of sterilizing the ordinary syringe renders it advisable 

Fig. 26. 



Blood aspirator. (Half size.) 

to employ a special apparatus without joints and permitting the 
adjustment of the needle on a ground-glass orifice (Fig. 26). 

The other end of the tube, considerably narrowed and bulbed, is 
plugged with cotton, and over it a rubber tube is slipped, through 
which the blood is sucked by the operator. The glass tube and 
needle are inclosed in a glass case, sterilized by heat, and kept ready 
for use. Such an apparatus — a modified form of one devised by Dr. 
James — has been made for the writer by Stohlmann, Pfarre c'c Co., 
New York City. 



68 GESERAL PHYSIOL OGY AXB PA THOL G Y. 

Operation. The blood should be drawn from the median basilic 
vein. The skin of the arm must be thoroughly washed with soap 
and water, cleaned with alcohol, and sterilized with bichloride solu- 
tion 1 : 500, or formalin 5 per cent. 

In most female subjects an Esmarch bandage must be applied at 
the axilla to render the basilic vein prominent, but in many male 
subjects this is unnecessary. It is better to incise the skin over the 
vein before inserting the needle, but this precaution is not essential 
under ordinary circumstances. When the needle enters the vein 
obliquely the blood should flow into the tube, and the flow may be 
hastened by suction through the rubber tube. 

At least 10 c.c. should be drawn, a quantity which is usually of 
no consequence to the patient. The elbow may be snugly bandaged 
after the operation. 

Preparation of Cultures. Before clotting the blood should be 
distributed in culture media. The medium chosen depends upon 
the particular organism which one expects to demonstrate. For the 
usual pathogenic species, staphylococcus, streptococcus, typhosus, etc., 
ordinary bouillon suffices, but for the gonococcus, ascitic broth should 
be preferred. 

The dilution of the blood should be considerable, and for 10 c.c. 
of blood it is advisable to employ at least 300 c.c. of broth. 

Unusual care should be employed at every step of the process to 
prevent contamination. 

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TECHNICS. 69 

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70 GENERAL PHYSIOLOGY AND PATHOLOGY. 

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CHAPTEK II. 

CHEMISTRY OF THE BLOOD. 
THE CHEMICAL COMPOSITION OF RED BLOOD CELLS. 

Ix the analyses of Schmidt, Hoppe-Seyler, and Judell the red 
cells were separated from the serum by the addition of salts 
(NaaSOj, XaCl), a procedure which considerably alters the chemical 
composition of cells and plasma. The accuracy of their results, 
which are the best available^ is therefore only approximate. 

The specific gravity of red cells is usually about 1088, They 
contain about 90 per cent, of oxyhemoglobin and a small proportion 
of a globulin-like albumin (nucleoproteid) coagulating at 75° C. 
There are also traces of lecithin and cholesterin. The principal salts 
are phosphates of Na, K, Ca, and Mg, and chloride of K, whereas 
in the serum the chief salt is NaCl. 

In cholera, dysentery, and dropsy, Schmidt found the red cells to 
be of increased specific gravity in proportion to the duration of the 
exudative process, while their chemical analysis showed that they 
participate in the changes which first affect the serum, losing first 
water, then salts, and finally albumin. More recently v. Jaksch,^ 
after establishing the normal content in N of the red cells, followed 
the variations in this principle in various diseases. He found very 
marked and irregular variations both in health and disease, which 
indicate that the method used (determination of total N) was unre- 
liable. 

Biernacki, estimating the dry residue of red cells settled after the 
addition of sodium oxalate, found a normal residue of 29.28 to 30 per 
cent. ; in carcinoma of the esophagus, 27.9 per cent. ; in tabes with 
anemia, 25.51 per cent. ; in chlorosis (Hb 25 per cent.), 22.24 per 
cent. ; in chronic nephritis (Hb 20 per cent.), 22.88 per cent. Among 
the important observations of Biernacki's are the increased content 
in water of the red cells in hydremia, the general parallelism between 
P2O5, Fe, and K, and between water and NaCl in the red cells. 

Hemoglobin (Hb) and its Derivatives. 

Hemoglobin belongs to the group of proteids, containing about 96 
per cent, of albumin and 4 per cent, of an iron-holding pigment, 
hemochromogen. Hb exists in the red cells in combination probably 
with the nucleoproteid of the stroma. The nature of this union is 
not certainly understood, but it renders Hb comparatively insoluble, 
greatly concentrated, and capable of actively forming unstable com- 
pounds with oxygen (Hoppe-Seyler, Gamgee). 



I 



72 GENERAL PHYSIOL OGY AND PA THOL OGY. 

Its chemical composition is very complex and apparently variable, 
but its spectroscopic relations are constant. In the circulation it 
exists principally as reduced Hb in the veins, and in molecular union 
with oxygen as oxyhemoglobin, in the arteries. One gramme of satu- 
rated oxyhemoglobin yields about 1.16 c.c. of oxygen, but in the cir- 
culation the degree of saturation with oxygen varies, and in health 
is never complete. Meyer and Biarnes found in the arterial blood 
of a dog 76 per cent, of saturation with oxygen ] after a large hemor- 
rhage it rose to 85 per cent, of saturation, while after inducing CO 
poisoning it rose to 90 per cent. Limbeck found 97 per cent, of 
saturation with oxygen in the blood of a dog poisoned with potassium 
chlorate. It thus appears that with a relative loss of functionating 
Hb the demands of the system may cause a more complete saturation 
of the blood with oxygen than exists in health. 

Oxyhemoglobin is bright red in color, and forms with difficulty 
yellowish red rhombic crystals. These crystals are very soluble in 
water and in very dilute solutions of alkaline carbonates, but when 
treated with strong alcohol they are modified and become insoluble 
(parahemoglobin of Nencki). They are insoluble in ether, chloroform, 
benzol, or carbon disulphide. Oxyhemoglobin is absolutely non- 
diffusible (Gamgee). 

Hemoglobin (reduced Hb) is dichroitic. In thick layers or in thin 
layers of concentrated solutions it presents a dark cherry -red color, 
while very dilute solutions exhibit a green tint (Gamgee). This 
dichroism is characteristic of the blood of simple asphyxia. Eeduced 
Hb is more soluble, but less easily crystallizable than oxyhemoglobin. 

Methemoglobin is brownish red in color, readily soluble in water, 
and crystallizes in brownish red needles, prisms, and hexagonal 
plates. It contains the same proportion of oxygen as oxyhemoglobin, 
but in much firmer and probably in chemical union. Methemoglobin 
is found in the blood chiefly in cases of poisoning by a variety of 
substances, the so-called " blood poisons.^' Tschirkoff claims to have 
found it in Addison^s disease, and Ruyter has recognized a very 
similar but not identical coloring matter in a case of malignant 
edema. 

Hemoglobinemia, a solution of Hb in the plasma, a normal condi- 
tion in the blood of some vertebrates, is in man always pathological, 
and results from lessened resistance on the part of the red cells and 
from abnormal states of the plasma. The former condition is prob- 
ably concerned in cases of paroxysmal hemoglobinemia and in the 
destruction of blood which follows general burns (Lichtheim, Murri, 
Chvostek, Silberman), while the latter condition exists in the hemo- 
globinemia of acute poisonings and in cases referable to increased 
globulicidal power of the serum. 

Carbonic oxide Hb is a firm compound of Hb and CO, and imparts 
a bluish red or rose-red color to the blood. Its crystals are similar 
to those of oxyhemoglobin, but more bluish and less soluble. In 
cases of poisoning by the inhalation of fire-damp or illuminating gas, 
CO-Hb is formed in considerable proportion and the respiratory 
capacity of the blood is largely destroyed. CO-Hb persists in the 



CHE3nSTBY OF THE BLOOD. 73 

blood for several days^ in cases that recover, and for a much longer 
period in fatal cases. 

Hematin, one of the advanced decomposition products of Hb, is a 
dark brown or blackish, non-crystalline solid, decomposed at 180° C. 
It is insoluble in water, dilute acids, alcohol, ether, and chloroform, 
but dissolves in acidified alcohol and ether, and readily in dilute 
alkalies. It is found in old blood transudates, in the feces where 
digestive fluids have acted npon blood, and in the urine in cases of 
arsenical poisoning. Crystals of hemin, or the hydrochlorate of 
hematin, are formed in Teichmann^s test. 

Hematoidin is a crystalline derivative of Hb, found in old blood 
extravasations. It crystallizes in orange-colored rhombic plates, is 
soluble in chloroform, ether, carbon di sulphide, and ammonium sul- 
phide, contains no iron, and gives no absorption bands, although 
absorbing most of the violet end of the spectrum. It is generally 
regarded as identical with bilirubin. 

Hemosiderin is an amorphous iron-holding product of the decom- 
position of Hb, and is abundantly found in the viscera in disease 
accompanied by much destruction of blood. It is probable that 
when red cells are disintegrated hemosiderin is formed by the action 
of living cells upon Hb, while hematoidin originates apart from any 
cellular activities (Perls, Thoma, Ziegler). Hemosiderin is black- 
ened by ammonium sulphide and turned blue by acidified potassium 
ferrocyanide. 

Melanin is a yellowish brown or black pigment produced by the 
action of the malarial parasite upon Hb. It is insoluble in water, 
alcohol, ether, chloroform, carbon disulphide, and acids in moderate 
strength, but is destroyed by heat, and is soluble in strong alkalies 
and in ammonium sulphide. It fails to yield the microchemical 
reactions of iron, and probably contains no iron. 

The term " melanin " is also loosely applied to a variety of black 
pigments occurring in the body, some of which contain iron but 
whose origin is uncertain. 

From " antialbumid," formed by heating egg-albumin with 3 per cent. 
HjSOi for ten hours at 100° C, and from hemipeptone, Chittenden and Albro 
produced black melanin by digesting these substances with 10 per cent. 
H2S0i and boiling for seventy-nine hours. The change they believe to 
consist in a process of hydrolytic cleavage. Sulphur and fatty acids were 
thrown off in the process, and the melanin was found to contain C, H, N, and S. 



THE CHEMICAL COMPOSITION OF LEUCOCYTES. 

Attempts to determine the chemical composition of leucocytes 
have been made by analyses of leukemic blood, of pus, and of fresh 
lymphoid tissue. In all of these it cannot be doubted that abnormal 
products were constantly present, so that the chemical composition 
of normal leucocytes cannot be learned by such methods. Probably 
Lilienfeld's analyses^ of lymphoid tissue furnish the most reliable 
data. 



74 GENERAL PHYSIOLOGY AND PA THOLOGY. 

In cadaveric leukemic blood various fatty acids have been isolated, 
and lecithin, a normal constituent of blood, has been found in ex- 
cess. Glycogen has been repeatedly isolated in this and other con- 
ditions. 

In fresh pus, Miescher found five different forms of albumin, an 
abundance of lecithin, and cholesterin, phosphates of Na, K, Ca, 
Mg, Fe, and chloride of Na. 

In analyses of the thymus gland in calves Kossel and Lilienfeld 
isolated various albumins, principally nucleins, lecithin, and choles- 
terin, besides about 3 per cent, of inorganic principles. In older 
cells they believe that secondary products develop in the form of 
glycogen, protagon, and fats. 

The nuclein of Kossel is a combination of the organic nucleinic acid which 
contains phosphorus, with albumin, and in the leucocytes is found in com- 
bination with another albuminous body, histon, with which it forms nucleo- 
histon. Under certain conditions Kossel and Lilienfeld believe that nucle- 
inic acid becomes free iu the cells, and exerts bactericidal action before and 
during phagocytosis. 

The nudeins are bodies obtained from animal (or vegetable) cells 
after digestion with pepsin to which they are resistant. They are 
rather insoluble in water, alcohol, and ether, give the biuret and 
Millon's reactions, and acting as strong acids and uniting with bases, 
they may be identified from the basic albumins by their tinctorial 
qualities. Boiled with dilute acids they yield ^^ nuclein bases ^^ or 
xanthin bodies ; or treated with alkali they yield albumin and 
nucleinic acid. They are rich in phosphorus and iron, Nucleinic 
acid is of variable composition, but that from the calf 's thymus is a 
combination of a xanthin body with a complex phosphoric acid 
(Hammarsten). 

Milroy and Malcolm have demonstrated some peculiar reactions of the 
granules of leucocytes. They found that weak watery solutions of sodium 
carbonate or of acids remove the pseudoeosinophile granules. Injections of nu- 
cleinic acid reduce the number of pseudoeosinophile and eosinophile granules 
and cause them to become basophile. This change they explain on the theory 
that the granules are composed of a nucleoproteid and an albumin, the latter 
being removed by the nucleinic acid. The change being most marked in the 
pseudoeosinophile granules, they conclude that in these granules the albumin 
is less firmly bound than in eosinophile. The complete solution of the baso- 
phile residue of the granules seemed to be accompanied by an increase of 



THE CHEMICAL COMPOSITION OF BLOOD PLATES. 

Since the true nature of blood plates has been at least partly shown 
the chief inquiry concerning them has related to their chemical com- 
position. Lowit has strongly maintained that they are composed of 
globulin, a claim which is probably true of some of the bodies which 
appear in coagulating shed blood and which must be classed with 
the blood plates of different origins. 



CHEMISTRY OF THE BLOOD. 75 

Lilienfeld^ regards the substance of blood plates as belonging to 
the uucleo-albumins, and identifies them with the remnants of the 
nuclei of leucocytes, basing this opinion on their content in phos- 
phorus, their resistance to digestion by pepsin, and their micro- 
chemical reactions. These observations may be regarded as definitely 
settling the question of their chemical composition, but do not prove 
their exclusive origin from leucocytes. 



The Serum. 

The Albumins of the Serum. Blood serum contains two albu- 
minous bodies, serum albumin and serum globulin, which together 
form 7.62 per cent. (Hammarsten) or 8.26 per cent. (Schmidt) of 
the weight of normal serum. 

The quantitative changes in these principles in disease are not 
usually very marked, owing to their relatively slight diffusibility. 

From the studies of Becquerel and Rodier, Schmidt, v. Jaksch, 
Limbeck and Pick, it has been shown that the albumins of the 
serum are considerably diminished in severe anemias, and in nephritis 
or endocarditis with dropsy, but that in most severe infectious dis- 
eases they are but slightly reduced and bear a fairly constant rela- 
tion to the other solids of the serum. If temporarily reduced by 
some exudative lesion, as in diarrhea, dysentery, etc., they are soon 
replaced if the disease continues. 

Becquerel and Rodier, however, found the albumins much reduced 
in puerperal septicemia, and Schmidt found a marked increase in the 
concentrated blood of cholera, v. Jaksch,^ determining the total 
N of the serum, found slight variations in many acute and chronic 
diseases, but a well-marked loss in leukemia, pernicious and secondary 
anemia, and chlorosis. Limbeck, using the same method, found less 
marked changes in cases of anemia. 

The ratio of serum albumin to serum globulin, on the other hand, 
varies much more than does the total quantity of albumin in the 
serum. The normal limits are placed by Limbeck and Pick, for 
globulin, 16.9 to 38.3 per cent., for albumin 61.7 to 83.1 per cent, of the 
total albumin of the serum. When such wide limits may be found 
in normal subjects it is difficult to attach much importance to very 
considerable changes demonstrated in disease, as reported by Estelle, 
Hoffman, Halliburton, and Mya and Yiglezio. In a considerable 
series of observations in various diseases Limbeck and Pick succeeded 
in showing only that serum globulin, the less diffusible principle, is 
less subject to change than is serum albumin, but they were unable 
to establish any other general rules. 

The inorganic salts of the serum include phosphates, chlorides, 
carbonates, and sulphates, but in what proportion or form the alkalies 
and earths are combined with these acids is not definitely known. 
Sodium and potassium are combined especially as neutral chlorides, 
partly as phosphates and carbonates. Pathological variations in the 
phosphates of the serum are of slight degree and importance, so far 



76 GENERAL PHYSIOLOGY AND PATHOLOGY. 

as is known, probably on account of their occurrence in scant quantity 
and their relative lack of diffusibility. A retention of phosphates in 
the blood of pathological grade has not been demonstrated. The 
variations in the chlorides of the serum investigated by Schmidt, 
Biernacki, and Limbeck have not been found extreme, nor of notable 
pathological import, although this principle is chiefly responsible for 
the isotonic relations of cells and serum. A high percentage of chlo- 
rides is usual in anemias. 

The specific gravity of the serum in disease varies slightly from 
the normal limits, 1025 to 1030 (Hammerschlag, Limbeck). AVhile 
Becquerel and Rodier and Hammerschlag found the specific gravity 
of the serum normal in chlorosis but reduced in secondary anemia, 
Limbeck found it low in both (1021 to 1023). Li infectious diseases 
Becquerel and Rodier found the serum of normal gravity. 

The color of human serum is yellowish with a slight greenish 
fluorescence, but after a hearty meal the increased quantity of fat 
may yield a cloudy or whitish color. The coloring matter of normal 
human serum belongs to the group of luteins or lipochromes (Ham- 
marsten). It is extracted by alcohol and by ether, yields a blue 
color with iodine and sulphuric acid, and on spectroscopic analysis 
causes an absorption of the violet and part of the blue, w^hich is 
unaffected by reducing or oxidizing agents. Icteric serum causes 
more complete absorption, beginning sharply in the blue (Lim- 
beck). 

When, from lessened resistance of the red cells or abnormal con- 
ditions of the plasma, red cells are dissolved the serum contains Hb 
in solution (hemoglobinemia), as occurs principally in malaria, par- 
oxysmal hemoglobinuria, septicemia, and with the blood poisons. In 
jaundice the serum has a characteristic orange-yellow color and 
bilirubin is readily detected. 

Hemolytic Properties of Human Blood Serum. Maragliano 
(1892) first investigated the hemolytic power of pathological blood 
serum upon the red cells of human subjects (isolysis), finding that 
the serum in many cases of primary anemia, leukemia, purpura, 
pneumonia, malaria, typhoid fever, cirrhosis, etc., possessed in vary- 
ing degree the power of dissolving healthy red cells. In the solution 
he obtained the spectrum of hematoidin. Heating to 50° to 53° C. 
did not destroy this hemolytic property. Various later writers have 
confirmed and extended these observations, and suggested various 
explanations of the toxic effects of blood serum, but the systematic 
study of the subject has been possible only since the contributions of 
Bordet and Ehrlich on the nature of hemolysis. Many of the earlier 
studies probably deal with other forms of hemolysis than those dis- 
cussed by Bordet and Ehrlich. 

Halpern (1902) reviews the subject to date, finding considerable 
but rather inconstant variations in the hemolytic power of blood 
serum in disease, both upon human and upon rabbit cells. In 
typhoid fever hemolysis was usually increased, and in septicemia it 
was decreased ; but in most other conditions it varied slightly from 
that of normal blood. (See section on Hemolysis.) 



CHEMISTRY OF THE BLOOD. 'J'J 



THE WHOLE BLOOD. 



Albumins. The albuminous principles of normal circulating 
blood include hemoglobin, serum albumin, serum globulin, and 
fibrinogen. In shed blood a nucleoproteid exists which is probably 
derived from the nuclei of leucocytes, probably also from red cells, 
which combines with calcium salts to form the fibrin ferment, and 
which is called '^prothrombin.'' Traces of albumose have been 
found in the blood in various diseases, and other nitrogenous princi- 
ples, occasionally present and commonly reckoned with albumins, are 
urea, uric acid, and xanthin bodies. Varying considerably with the 
method of determination, the proportion in which these elements 
exist in the blood has been placed for the entire group by v. Jaksch^ 
at 22.62 per cent. ; bv Limbeck at about 25 per cent. ; by Schmidt 
at 10.82 to 16.63 per^cent. 

A relative increase of total albumin is seen, accordiug to v. Jaksch, 
in diseases accompanied by marked loss of fluids, as in cholera and 
severe diarrhea, but an absolute increase has not been demonstrated. 
In infectious diseases the albumins are moderately reduced, even 
when the number of red cells remains normal (typhoid fever). In 
nephritis there is usually but not always a reduction. In endocarditis 
there is little change. In chlorosis, pernicious anemia, and leukemia 
the total albumins of the blood are constantly diminished, but in 
secondary anemia the diminution usually noted sometimes fails. 
V. Jaksch found his lowest proportion, 8.46 per cent., in a case of 
gastric cancer. 

Peptone has been demonstrated in the blood of leukemia by Ludwig, 
V. Jaksch,^ and Freund and Obermayer, and deidero-albumose by 
Matthes. These observations were made on blood from the cadaver. 
Devoto and Wagner, who examined blood obtained during life, both 
failed to find peptone. The suspicion that the peptone previously 
demonstrated was of postmortem formation was followed up by 
V. Limbeck in a case of myelogenous leukemia. In the fresh blood 
no peptone was found, but in a specimen that had stood at room 
temperature for forty-eight hours albumose was demonstrated, but 
its exact character was not determined. The patient died three 
weeks later and deutero-albumose was demonstrated in the blood of 
the cadaver, v. Jaksch states that peptone (albumose ?) is found in 
leukemic blood only when eosinophile cells are abundant. Freund's 
observation that peptone is found in the blood in cases of sarcoma 
but not in cases of carcinoma has not yet been confirmed. 

The addition of small quantities of peptone to plasma in vitro 
reduces its content of COg and its coagulability, and it seems prob- 
able that if peptone (or albumose) exists in the circulating blood a 
similar influence is exerted, inty^a vitam, by its presence. 

Quantitative estimation of total albumin of the blood may be 
accomplished by one of two methods. 

1. By precipitating the albumins by excess of alcohol, and weigh- 
ing the dried precipitate. 



78 GENERAL PHYSIOLOGY AND PATHOLOGY. 

2. By estimation of total N by Kjeldahl's method and multiplying 
the result by 6.25 (v. Jaksch). 

By the first method an uncertain quantity of inorganic matter is 
carried down which cannot be thoroughly removed by washing, and 
which therefore disturbs the result. 

In the second method N is derived from other principles besides 
albumins, and, as Limbeck and Pick have shown, there may be a 
difference of 10 to 20 per cent, in the results of the two methods. 

Most of the nitrogenous principles other than albumins are soluble 
in alcohol, and some of the sources of error in this method are there- 
fore removed by estimating the total N of the alcoholic precipitate. 
V. Jaksch has determined that by multiplying the percentage of N 
by 6.25 the average percentage of weight of albumin is obtained. 
Limbeck and Pick, after investigating the ratio between N and the 
weight of albumin from Avhich it was derived, concluded that 
v. Jaksch's figure is sufficiently reliable in the great majority of 
cases, but that considerable inaccuracies may result in the cases of 
venous stasis, nephritis, and especially uremia, in which nitrogenous 
principles in the blood other than albumins are increased. 

The determination of total N by KjeldaliFs method is generally 
employed in estimating the albumins of the blood. The method 
may be found fully described by Halliburton, Chem. Phys. and Path., 
and Sutton, Volumetric Analysis. 

Inorganic Principles of the Blood. 

The Blood Ash. After incineration of two specimens of normal 
blood Schmidt found 0.84 per cent, and 0.91 per cent, of ash. This 
quantity was increased to 1 per cent, in a case of cholera, but the 
relation of ash to dry residue remained normal, 3.1 to 3.5 per cent. 
In the watery blood of nephritis, however, the ash was relatively 
much increased (6.5 per cent.). 

Chemical analysis of the blood ash in health and disease have 
shown that pathological importance attaches principally to variations 
in the chlorides, phosphates, and the iron of the blood. 

With regard to the chlorides (principally NaCl) the law has been 
established that the larger the proportion of plasma the greater is the 
percentage of chlorides in the blood. In pneumonia the chlorides are 
low, probably owing to diminished ingestion and the effects of an 
exudative process which drains the blood of a considerable quantity 
of salts. In typhoid fever and erysipelas a reduction usually exists 
which is neither so marked nor so constant. In nearly all forms of 
anemia the proportion of chlorides is high, following the rule above 
stated. Yet Limbeck found normal proportions in two cases of 
chlorosis, which he refers to diminished salts in the red cells, and 
Biernacki refers to cases of severe anemia with normal chlorides, 
which he also explains from the loss of red cells. Becquerel and 
Kodier found considerable variations, but a normal average in chlo- 
rides in six cases of chlorosis. 

From the known influence upon the urinary chlorides of dimin- 



CHEMISTRY OF THE BLOOD. 79 

ished ingestion of food, vomiting, diarrhea, and exudation, it appears 
probable that these factors may to some extent affect the chlorides of 
the blood, for in many of the available analyses of the blood ash in 
general diseases there are numerous contradictory results (tubercu- 
losis, syphilis, cancer). 

The phosphates exist as neutral or alkaline salts of Na, Ca, Mg, 
in the plasma and in various combinations (lecithin, nuclein) in the 
red and white cells. Few facts of importance have been established 
in regard to the variations in these principles of the blood. 

Biernacki demonstrated a considerable diminution of P2O5 in anemia, and 
at the same time a certain parallelism between P2O5 and K in these condi- 
tions. In leukemia, Freund and Obermayer found an increase in P2O5 and 
Na, while the K was diminished. 

The alkalies Na and K are principally combined with CI in the 
blood, but Xa is united in considerable proportions as phosphates 
and carbonates. The sodium salts, being found principally in the 
plasma, are subject to marked quantitative variations, being usually 
increased in watery blood. Potassium being located chiefly in the 
red cells is diminished in most hydremic conditions, and not alone 
in scurvy as suggested by Garrod. Sodium carbonate is probably 
the next most abundant salt of the plasma after sodium chloride, and 
to this salt mainly the plasma owes its alkalinity and its power to 
absorb COg. 

Iron. The iron of the blood is principally found in the hemoglo- 
bin, a compound of albumin and iron containing, in human blood, 
about 0.42 per cent, of iron. It also occurs in traces in the plasma, 
and is found in relatively large proportion in nuclein (Hammar- 
sten). The percentage of iron in normal blood is placed by Limbeck, 
from the results of several analyses, between 0.056 and 0.058. Jolles 
found variations between 0.0413 and 0.0559 per cent., and Hladik an 
average of 0.0425 per cent., using the ferrometer devised by the 
former. 

While the principal depot of iron is in the Hb of the red cells, and 
the quantity of iron is closely proportionate to the percentage of Hb, 
the ratio between the two is often disturbed, because all iron of the 
blood does not form colored compounds. A further discrepancy 
between the Hb per cent, (after Fleischl) and the iron content of the 
blood results from the presence of iron-free pigments, as the lutein of 
Thudicum or the hydrohiliruhin of Maly. 

Thus Biernacki found that direct quantitative estimation always yields more 
iron than the computation from the percentage of Hb, after Fleischl. Some- 
times twice as much iron was found as was to be expected from the Hb per- 
centage. Similar results have been obtained by Jolles and Jellinek. It seems 
probable that the general introduction of a practical clinical method of esti- 
mating the iron of the blood may develop some new facts of interest in the 
pathology of the blood. Thus, Jellinek found in a case of purpura hemor- 
rhagica that iron-free pigment was apparently absorbed from extravasations, 
since the Hb registered 50 per cent, after Fleischl, but only 38 per cent, as 
computed from the iron-content. Also in a case of malaria immediately 
after a paroxysm the Hb sank 10 per cent, while the iron remained con- 
stant. 



80 GENERAL PHYSIOLOG Y AND PATHOLOGY. 

Estimation of the Inorganic Principles of the Blood. It falls 
outside the scope of the present volume to consider the details of 
inorganic quantitative analysis of the blood. 

For the estimation of Fe, however, reference should be made to 
the clinical method and results of Jolles. This method permits the es- 
timation of Fe within fifteen minutes, and with considerable accuracy. 
The apparatus is offered by Reichert's agents in this country and is 
accompanied by full directions for use. 

Mackie has described clinical methods of estimating Fe and phos- 
phoric acid in a drop of blood, to which the reader is referred. 
("Iron/' Lancet, 1898, vol. i. p. 219; "Phosphoric Acid,'' Lancet, 
1899, vol. ii. p. 484.) 

Urea in the Blood. 

Urea occurs in traces in normal blood (Picard) and in increased 
quantity in fevers (Gescheidlen), and when, as in nephritis, its excre- 
tion by the kidneys is imperfect. In uremia Munzer found 0.4 per 
cent, of urea in the blood, but the amount is regarded as insufficient 
to cause the toxic symptoms of this condition. 

Demonstration of Urea in Blood, v. Jaksch recommends the following 
procedure : 200 to 300 c.c. of blood are precipitated with three to four times as 
much alcohol, and after twenty-four hours the precipitate is repeatedly washed 
in alcohol. The alcohol is then evaporated, the residue treated with nitric 
acid, and the crystalline mass, secured after some hours, is dried between filter 
paper, dissolved in water, treated with barium carbonate till CO, ceases to 
form, dried on a water-bath, and extracted with hot alcohol. On evapora- 
tion urea is found in slender rhombic prisms. If secured in sufficient quantity 
the crystals may be treated with nitric acid and evaporated, when character- 
istic crystals of urea nitrate form. Or the biuret test may be employed, dis- 
solving the crystals in a little caustic potash, and adding a drop of dilute 
cupric sulphate. 

Various other methods may be found described in text-books of physiologi- 
cal chemistry — e. g., Gamgee. 

Uric Acid in the Blood. 

Scanty traces of uric acid have been demonstrated in normal blood 
(Picard, Abeles). Garrod found 0.025 to 0.145 per cent, during acute 
attacks of gout, and Salomon also found an increase in acute gout. 
V. Jaksch regards their methods as inexact. A moderate increase 
(0.08 per cent.) has been demonstrated in pneumonia and anemia 
(Salomon,^ v. Jaksch^), in cardiac and other forms of dyspnea, and 
in nephritis (v. Jaksch). Klemperer^ and Weintraud noted moderate 
increase in leukemia (0.09 per cent.), in nephritis (0.06 per cent.), 
and in uremia (0.19 per cent.), but failed to find any trace in three 
healthy subjects and in one case of pneumonia. 

Estimation of Uric Acid. — Garrod took 10 c.c. of serum from 30 c.c. to 35 c.c. 
of coagulated blood, added 10 per cent, of dilute acetic acid, and obtained crys- 
tals of uric acid on a thread placed in the fluid. In blood containing not 
less than 0.025 per 1000 of uric acid the thread was covered with crystals in 
twenty-four to forty-eight hours. These crystals should be submitted to the 
murexide test. 



CHE3nSTRY OF THE BLOOD. 81 

V. Jaksch recommends the qualitative and quantitative estimation of uric 
acid by means of the Ludwig-Salkowski method employed in urinary analysis. 
The blood is prepared for this method as follows : 100 c.c. to 300 c.c. of blood 
are diluted three to four times with water, heated on the water-bath until coagu- 
lation begins, when it is feebly acidified by acetic acid (s. g. 1.0335). After 
fifteen to twenty minutes it is filtered, the precipitate washed with hot water, 
boiled again after feebly acidifying, cooled and filtered. A little sodium 
phosphate is now added to the filtrate, which is then submitted to the Ludwig- 
Salkowski method. For a full description of this method, see Simon's Clinical 
Diagnosis. 

Glucose in the Blood. 

Xormal blood always contains traces of glucose, which may be 
increased by diet rich in carbohydrates, and is diminished by mus- 
cular exercise and hunger (Seegen, Chauveau and Cavazanni, v. 
Mering). Limbeck found in the blood of two healthy subjects, five 
hours after eating, 0.075 per cent, and 0.089 per cent, of glucose. 
Freund and Trinkler find that glucose is very considerably increased 
in the blood in cases of carcinoma, readily reducing cupric oxide 
when freed from albumins, which cannot be accomplished with the 
blood of any other disease except diabetes. In one case of cancerous 
cachexia Trinkler found 0.3 per cent, of glucose, which reaches the 
limit stated by Claude Bernard to be capable of producing diuresis. 

In diabetes the quantity of glucose in the blood is subject to great 
variations, according to the character and progress of the disease. 
Hoppe-Seyler found in one case 0.9 per cent. 

Estimation of Glucose in the Blood. A weighed quantity of blood is 
freed from albumin by boiling with an equal quantity of sodium sulphate 
and filtering. The precipitate is well washed and the presence and quantity 
of glucose in the filtrate determined by Fehling's solution or by polarimetry. 
A certain amount of sugar is carried away by the precipitated albumins, and 
unless the blood is fresh, the action of the glycolytic ferment may cause serious 
error in the result. 

Glycogen in the Blood. 

The long discussion regarding the feasibility of demonstrating 
glycogen in the blood by chemical methods has led to many contrary 
opinions, but in recent years positive results have been more constant 
(Salomon, Frerichs, Cramer, Lepine and Barral, Huppert, Czerny). 

The microscopic test on specimens dried in the air and stained by 
iodine, after Ehrlich's suggestion, has given more uniform results. 
Gabritschewsky, using this method, found intracellular and extra- 
cellular glycogen in the blood of both healthy and diseased persons. 
Extracellular glycogen , in the form of fine or coarse granules (Iju to 6//) 
he found to be the only form usually present in normal blood ; and 
it was increased in diseases in which intracellular glycogen was abun- 
dantly present. He states that extracellular glycogen is derived 
from the disintegration of leucocytes, but offers no evidence to prove 
this origin. The glycogen was found in the bodies of neutrophile 
leucocytes in cases of diabetes and leukemia, and in the plasma in a 
considerable variety of other diseases. The results of his experi- 
ments, injecting sugar and peptone into the blood of animals, indicate 



I 



82 GENERAL PHYSIOLOG Y AND PATHOLOGY. 

that the leucocytes are capable of transformiug both sugar and pep- 
tone into glycogen. Livierato also found extracellular glycogen in 
normal blood, but failed to discover any in the leucocytes in diabetes. 
From his clinical observations he concludes that the glycogen of the 
blood is increased in febrile cases with an active exudative lesion and 
with leucocytosis. In typhoid fever he found only extracellular 
glycogen. 

Czerny's studies added considerably to the knowledge of the subject. He 
found the increase of glycogen in exudative processes with leucocytosis. In 
the blood of children with cachectic leucocytosis he found an almost equal 
quantity. In two or three dogs exposed to prolonged cold he found that 
glycogen appeared in the leucocytes after twenty-four hours, and persisted for 
several days. From the severe disturbances of respiration following section 
of both vagi, or pneumothorax artificially introduced, as well as in severe 
anemia from hemorrhage, he found a marked increase in glycogen. An inter- 
esting inquiry of Czerny's related to the exact chemical nature of the brown 
staining granules demonstrated by iodine, a reaction common to both gly- 
cogen and amyloid. That these brown granules are glycogen is indicated 
by (1) their reaction to iodine; (2) by the disappearance of their brownish 
stain on heating (Barfurth), and (3) by their complete digestion by saliva 
(Czerny). On the other hand, Czerny points out that pure glycogen is soluble 
in water, while the glycogen of leucocytes is insoluble in water (as the writer, 
also, has found), that iodine with dilute sulphuric acid colors these granules 
violet, which is the reaction of amyloid; and, finally, that in dogs suff"ering 
from prolonged suppuration whose blood continually shows abundance of 
"glycogen," the viscera, on the other hand, develop extensive amyloid changes. 
These observations indicate that the brownish staining granules are not pure 
glycogen, but a comparatively insoluble compound of glycogen with some other 
substances, or else an intermediate product between glycogen and amyloid. 

Caminer failed to find any glycogen in normal blood, and in disease very 
rarely found it in the plasma. He distinguished three stages of the deposit 
in leucocytes: (1) the presence of a light, diffuse mahogany stain; (2) the 
presence of a few isolated globules; (3) the complete transformation of the 
body of the cell into glycogen. In cases of extreme sepsis, all stages were 
seen ; in pneumonia glycogen was usually present, but never in the third 
stage of its formation ; in phthisis only the first stage was found ; and in 
rheumatism it was absent. In cases of carcinoma it was found only when 
suppuration occurred. In four diabetics none was found, but in a case of 
diabetic coma it was abundant. It was absent in most cases of carcinoma, 
in chlorosis, in two cases of leukemia, and in secondary anemia from hemor- 
rhage. From experimental studies, he finds that three factors are concerned 
in the glycogenic degeneration of leucocytes : (1) fever, (2) leucocytosis, (3) 
toxemia, of which the last is most potent. 

T. Dunham found the glycogenic degeneration of leucocytes a valuable aid 
in the diagnosis of suppuration, and introduced the term " iodophilia." Locke 
has contributed extensive clinical observations on the occurrence of glycogen 
in leucocytes. He found an extracellular reaction, especially in the blood 
plates, in all cases, and regards this occurrence of no clinical importance. In 
septicemia an intracellular reaction was marked and constant. In abscess it 
was present in 22 of 25 cases, but disappeared in forty-eight hours after drain- 
age of the pus. The three negative cases were very small abscesses without 
fever or leucocytosis. In appendicitis, peritonitis, and empyema it was abun- 
dant when pus was forming, but otherwise absent or slight. In serous pleurisy 
no reaction occurred even with high fever. In 49 cases of pneumonia it was 
constant and persistent. In malaria 22 of 29 cases gave a positive reaction. 
In 17 of 42 cases of typhoid fever the reaction was present, but referable to 
inflammatory complications. After perforation the reaction increased within 
six hours. In tuberculosis it was absent or faint if there were no suppurative 
complications. In diabetes a positive reaction occurred only with coma or 
gangrene. In pernicious anemia a very faint reaction was occasionally seen. 



CHE3nSTEY OF THE BLOOD. 83 

Xumeroiis other reports on the occurrence of glycogen in leuco- 
cytes have appeared, showing that the subject is of considerable 
clinical interest and sometimes of value in diagnosis. Regarding 
the microscopic demonstration of extracellular glycogen, it should be 
mentioned that other principles, such as myelin, lecithin, and amyloid, 
stain brown with iodine. 

Lipemia. 

The occurrence of free fat (palmitin, stearin, olein) in the blood, 
both in health and in disease, has repeatedly been observed. While 
usually present in such small quantity as to be recovered in very 
small amounts from the ethereal extract, and recognized with diffi- 
culty by the microscope, it is sometimes so abundant as to give the 
blood a milky appearance (Gumprecht). Its physiological variations 
probably exceed the pathological, as it has been found very much in- 
creased in healthy individuals after a hearty meal. In disease its 
occurrence appears to follow no general rule, so that its real patho- 
logical significance remains doubtful, v. Jaksch, extracting the 
blood with ether and thereby including fat, lecithin, cholesterin, and 
a trace of nitrogenous compounds, found in three cases of diabetes 
0.05 to 0.16 per cent., in nephritis 0.1 to 0.5 per cent., in typhoid 
fever 0.16 per cent., and in pneumonia 0.15 per cent. It has also 
been found in increased quantity in phthisis, poisoning by carbonic 
acid, and in fat embolism after traumatism. 

Englehart found considerable variations in the ether extract of 
human blood in healthy subjects, viz., 0.101 to 0.273 per cent., 
average 0.194 per cent., while in cachectic subjects, although no 
greater variations were found, the average was lower than 0.174 per 
cent. In fasting dogs, Cohnstein and Michaelis found an average of 
0.121 per cent, in seven analyses, while after fatty diet the average 
rose to 0.153 per cent. 

Acetonemia. Lipacidemia. 

Deichmuller and v. Jaksch, by extracting the blood with ether 
and by distillation, have isolated a principle which gives the reaction 
of acetone, and which they found increased in many processes, espe- 
cially in fevers. Fatty acids have been found in the blood by 
V. Jaksch, in diabetic coma, leukemia, acute yellow atrophy of liver, 
and acute infectious diseases : /9-oxy butyric acid, in the cadaveric 
blood of diabetes, by Hougounenq ; and sarcolactic acid, in normal 
blood, by Gaglio, Spiro, and Berlinerblau. Limbeck doubts the 
reliability of these results, believing that fatty acids may develop 
from lecithin during the technical procedures followed in isolating 
these principles. 

Cholemia. 

The poisonous symptoms developed in cholemia have been referred 
by most authorities to the presence of biliary acids. Plinths state- 



84 GENERAL PHYSIOLOGY AND PATHOLOGY. 

ment that cholesteriu is the poisonous agent has not been accepted, 
although it lias been found in considerable traces in icteric blood. 

To the naked eye icteric blood may appear of yelloAvish red color, 
while in the serum or its foam small quantities of bile pigQient are 
readily detected by the peculiar yellowish tinge. On repeated heat- 
ing the yellowish red bilirubin changes to the green biliverdin. 

Diminished isotonic tension and increased resistance of the red cells 
are a peculiar character of the blood in jaundice. Limbeck found the 
tension of the cells reduced 0.4, 0.38, and 0.32 per cent. NaCl, and 
that of the serum 0.76 and 0.864 per cent. NaCl. The well-attested 
fact that in intense jaundice red cells are frequently dissolved by biliary 
principles, can, with some difficulty, be reconciled with this markedly 
hyperisotonic quality of the serum. Limbeck believes that bile acids 
affect the union of Hb with the stroma of the red cells, rendering 
the Hb more easily soluble, and thinks that the solution of red cells 
in jaundice, as well as in other conditions, depends on other than 
simple osmotic factors. 

Other characters of icteric blood are, according to Limbeck^s 
analyses, an increase of nitrogenous bodies (3.29 to 3.52 per cent.) ; 
diminution of chlorides of both blood and serum, which he refers to 
their displacement by biliary acids ; and a well-marked increase in 
the volume of red cells (Bleibtreu's method). 

Detection of Biliary Principles in the Blood. Well-marked 
cholemia may be detected by naked-eye inspection of serum or its 
foam. On heating to 50° C bilirubin may be changed to biliverdin. 

V. Jaksch has been able to demonstrate bilirubin in the blood when none 
was to be found in the urine, or when only urobilin existed in the urine, by 
the following procedure : A little blood obtained by a wet-cup is allowed to 
coagulate, and after one to two hours the serum is drawn off and forced by- 
aspiration through an asbestos filter. The froth of the filtrate is yellow if 
any bilirubin is present, and this yellow tinge becomes green on heating two 
or three hours at 35° C, if any minute traces of bile pigment are present. 
Or the blood may be coagulated slowly at 78° to 80° C. when the serum becomes 
greenish in the presence of minute traces of bile. 

BUiary acids may be demonstrated by Pettenkofer's method on 
serum prepared as follows : 

Albumins are removed by boiling or by alcohol, and the filtrate is treated 
with lead acetate, and with ammonia, which precipitates the acids with the 
lead compounds. The acids are then recovered, by washing the precipitate 
on a filter, boiling in alcohol, filtering, and decomposing the lead salts by 
carbonate of soda. The solution is again filtered, evaporated to dryness, and 
the acids extracted by boiling in absolute alcohol. Finally, on evaporating 
the alcoholic extract, biliary acids crystallize out, or an amorphous substance 
remains, from which the crystals may be obtained by extracting with ether. 

The Specific Gravity of the Blood. 

The specific gravity of the blood changes with the content of 
water, its most variable constituent, the proportion of salts, which 
are less variable, and the percentage of albumins, which are the last 
principle affected by pathological processes. 



CHEMISTRY OF THE BLOOD. 85 

The normal limits have been placed by Becquerel and Rodier between 
1.058 and 1.062 for men, 1.054 and 1.060, including both sexes; by 
Hanimerschlagj between 1.056 and 1.063, including both sexes; by 
Lloyd Jones, between 1.045 and 1 .066. Some of these discrepancies are 
doubtless referable to the differences between the methods employed. 

There are considerable ^physiological variations in gravity. Accord- 
ing to Lloyd Jones the blood of newborn infants shows the highest 
gravity, averaging 1.066 ; after the second week of life up to the 
second year the gravity sinks, 1.048 to 1.050 ; rising with men between 
thirty-five to forty-five years to 1.058, Avith women after the climac- 
teric, to 1.054 ; in old age the blood of both sexes approaches the initial 
high gravity of infancy. Limbeck finds an explanation of these 
progressive changes in the decreasing capacity of the tissues to absorb 
water. From forty-four estimations on his own blood Schmaltz 
found minimal variations at different hours of the day, from 1.061 
from 7 to 8 a.m., to 1.058, from 2 to 8 p.m. Muntz found a marked 
increase, 1.038 to 1.058, in the gravity of the blood in overfed sheep. 
Muscular activity, if accompanied by sweating, slightly decreases, 
sleep slightly increases the gravity (Schmaltz, Jones). Schmaltz 
found that meustruation is followed by a slight increase of gravity, 
while the slightly lower gravity of pregnant and parturient women 
has been frequently observed. 

For somewhat obscure reasons the gravity of the blood is increased 
by residence in high altitudes and a considerable difference (0.015) 
has been observed in the blood of animals pastured on mountain 
tops and those grazing in the valleys (Muntz, Viault, Glogner). 

In pathological conditions lowered specific gravity is a constant 
character of the blood in anemia. 

In chlorosis the change is usually referable to and proportionate 
with the loss of Hb, but Stintzing and Gumprecht and Siegel have 
shown that this parallelism is not invariable. In pernicious anemia 
the specific gravity and dry residue suffer more than the Hb, owing 
to loss of albumins from the serum. Extremely low gravity, in 
comparison with the lib-content, is characteristic of this condition. 
In leukemia the gravity is reduced as in simple anemia, but extreme 
reductions are seldom observed, owing to the increase of white cells 
and the presence of abnormal products soluble in the plasma. In 
secondary anemias there are numerous exceptions to the parallelism 
between specific gravity and Hb-content. These are found especially 
in diseases in which an exudative process drains the blood of albu- 
mins (dysentery), or when from edema there is relative hydremia of 
serum or red cells. 

In the infectious diseases the specific gravity of the blood depends 
upon associated conditions, such as profuse perspiration, diarrhea, 
exudation, etc., more than upon any specific property of bacteria to 
increase the water of the blood. That the power to impoverish the 
blood varies, however, with different infectious agents is strongly 
indicated by clinical observation. Grawitz's claim that tuberculin 
and the diphtheria toxin tend to increase the gravity of the blood, 
while the toxins of streptococcus and staphylococcus pyogenes tend to 



SQ GENEEAL PHYSIOLOGY AND PATHOLOGY. 

diminish it, is frequently confirmed by comparison of the blood in 
cases of miliary tuberculosis and uncomplicated diphtheria with that 
of septicemia. 

Although acute stasis is usually followed by marked increase in 
the gravity of the blood, yet in chroniG endoca7^ditis the variations 
observed are very irregular. General edema is usually associated 
with lowered gravity. 

The same observation applies to the blood of nephritis^ normal 
gravity being observed in many cases of chronic interstitial nephritis 
(Hammerschlag), while anemia and low gravity of the blood and 
edema of the tissues are nearly constantly associated with the large 
white kidney. 

Numerous studies of the blood oi pulmonary tuberculosis, including 
that of Grawitz, have failed to bring to light any uniform variations 
in gravity peculiar to the blood in this disease. As a rule, extreme 
reductions are not observed. 

In the cachexia of malignant neoplasms some of the lowest gravi- 
ties on record have been observed (1.030, 1.032, Lyonnet), especially 
in ulcerating and bleeding tumors of the stomach and uterus. 

In certain shin diseases (pemphigus, eczema, psoriasis, prurigo, 
morbus maculosus) an increased gravity of the blood has been noted 
by Schlesinger. In cases of general burns, Tappeiner, Baraduc, and 
Schlesinger have found very high gravities, 1.065 to 1.073, which, in 
cases that recovered, fell to normal in twenty-four hours. 

Finally, various drugs appear to exert a moderate but in no sense 
peculiar influence on the gravity of the blood. Purges, diaphoretics, 
and diuretics remove water from the system, and when this loss is 
not immediately replaced from the tissues the blood is temporarily 
concentrated. The action of mercury is somewhat uncertain, but in 
syphilis it appears to diminish the gravity after a short initial period 
of increase (Schlesinger). 

To recapitulate, it has been found that considerable variations in the 
water of the blood may under ordinary conditions be promptly equal- 
ized by the action of -the tissues on the one hand replacing a loss, or 
of the kidneys and skin removing an excess, so that the change in 
the blood is very transitory. Only when there is interference with 
these processes or when the demands upon them are excessive does 
a more or less permanent alteration in the gravity of the blood follow. 

On the other hand, when the albumins of the blood are affected, 
more marked and permanent changes are produced. In general, the 
content of the tissues in water and that of the blood are very closely 
interdependent. 

The Ferments of the Blood. 

In recent years the metabolic processes in the cells, both catalytic 
and synthetic, have been referred more and more to the agency of 
ferment-like bodies, many of which have been demonstrated in the 
blood. It falls outside the scope of this work to consider the rela- 
tions of the fibrin ferment and of the probable ferment action of the 



CHEMISTRY OF THE BLOOD. 87 

toxophore group of Ehrlicli^s complement, but some other special 
fermentative processes inherent in the blood or its cells deserve brief 
mention. 

Oxidase. The presence of an oxidizing ferment in the blood 
was first demonstrated by Schonbeiuj who located the ferment in the 
stroma principally of the red cells. Its importance in physiology is 
now fully recognized. 

Lillie has applied an interesting method of demonstration of an 
oxidase in leucocytes and red cells. When blood is mixed with an 
alkaline solution of «-naphthol or paradiamidobenzene, in equi- 
molecular proportions, the solution, at first colorless, becomes deeply 
tinted from oxidation, and many stained granules of oxidation prod- 
ucts are deposited about the nuclei of leucocytes and in the red cells. 

Lipase. The presence of a fat-splitting ferment in the blood has 
been claimed by Hanriot and others, but its existence is not fully 
proven (Jacoby). 

Proteolytic Ferment. Ascoli and Moreschi report that the 
washed sediment of sterile pus from empyema contains a proteolytic 
ferment. To the action of such a ferment in the leucocytes has been 
attributed the dissolution of the pneumonic exudate, in which, of 
course, the leucocytes are mingled with other cells and are dying. 

Glycolytic Ferment. The presence of a glycolytic property in 
normal blood has been long known. Lepine found that it depends 
on the red cells more than upon the plasma, and he elaborated the 
theory that diabetes results from the diminution or absence of this 
glycolytic feruient. It has been shown, however, that the glycolytic 
property of diabetic blood is not distinctly inferior to that of normal 
blood (Minkowski, Kraus). The experiments of Seegen and 
Arthus indicate that this property is not exerted during life, but is a 
cadaveric phenomenon, and that the extent of its action depends 
upon the time consumed in the examination of the specimen. This 
objection applies to present views regarding nearly all of the cell 
ferments and is not generally regarded as valid (Jacoby). 

Spitzer, in an exhaustive study, finds that a glycolytic ferment is 
present not only in red and white blood cells, but in all tissue cells ; 
that it is precipitated in active form by alcohol, and that its action is 
possible only in the presence of oxygen as contained in oxy-Hb. 

Diastatic Ferment. The study of the property of fresh blood to 
digest starch has lately been extended to the blood in various diseases. 
This property may be demonstrated by adding 1 c.c. of blood to 
50 c.c. of a solution of starch, allowing the mixture to stand a few 
hours- in the thermostat, when glucose may be demonstrated by 
Fehling's solution. 

Castellino and Pracca found that 2 c.c. of normal human blood added to 
50 c.c. of starch solution produced 0.07 per cent, of sugar in twenty-four 
hours, at 30° C. Arterial blood is more active than venous, and the fermenta- 
tion most active between 30° and 38° C, is inhibited at 75° C, and diminished 
bv slight changes in reaction (Cavazanni). Cavazanni and Pracca found con- 
siderably increased fermentative power of the blood in anemia, chlorosis, 
leukemia, pneumonia, malaria, nephritis, cirrhosis, and carcinoma, while in 
other cases of these and other diseases it was diminished. 



88 GENERAL PHYSIOLOG Y AND PATHOLOGY. 

The principal source of the diastatic ferment is placed in the red 
cells by Tiegel and Plosz, in the serum of Bial, and in the leucocytes 
by Castellino and Pracca. The last-named observers find that the 
diastatic property is closely related to the globulicidal and coagulative 
power of the blood ; that it increases after the blood is shed ; that it 
is inhibited by the addition of nuclein, and increased by sodium sul- 
phate and chloride. 

Tschereskoff was able to precipitate from blood by alcohol small 
amounts of a diastatic ferment which remained active forty -five days. 
It was more abundant in the serum than in the clot, and the presence 
of sodium oxalate did not destroy it. 

The Osmotic Relations of the Blood. 

When a drop of blood is placed in distilled water the red cells are 
promptly dissolved, but when blood is placed in a solution of salt of 
a certain concentration the red cells retain their Hb, and sink to the 
bottom of the fluid. The solution of the cells results from the law 
of osmosis, that when two solutions of different concentration are 
separated by an animal membrane the solutions pass through the 
membrane until the quantity of salt in each is equal. The force 
which leads to this interchange is called " osmotic tension/' and two 
fluids with equal content of salt are said to be ^' isotonic/' or of equal 
^' isotonic tension.'' Fluids are likewise said to be hype^^isotonic or 
hypisotonic when they contain greater or lesser quantities of diffusible 
salts than other fluids, and are capable of drawing water from or 
yielding it to such fluids, according to the laws of osmosis. 

A solution containing 0.46 per cent, of NaCl is just sufficient to 
prevent the solution of red cells in the average specimen of normal 
human blood (Limbeck), and the isotonio tension of human red cells 
may, therefore, be said to be 0.4-6 per cent. NaCL Yet when red cells 
are placed in a 0.46 per cent, solution of salt they absorb water and 
swell, although they do not yield up Hb, and when placed in strong 
solutions of salt, red cells shrink, yielding water to the fluid. Ham- 
burger finds that a 0.9 per cent, solution of salt causes neither swelling 
nor shrinkage of the red cells. This solution, therefore, represents the 
isotonic tension of the blood plasma, and is properly called the " normal 
salt solution.^' 

Any considerable lowering of the osmotic tension of the plasma 
must therefore lead to swelling of the red cells and eventually to 
their solution. The hyperisotonic quality of the plasma with refer- 
ence to the red cells is a physiological necessity, otherwise the inges- 
tion of a considerable quantity of water would cause the solution of 
many red cells. The exact limits of osmotic tension between which 
the red .cells suffer no alterations of volume are not known, but it is 
certain that they are often exceeded in pathological conditions. 
Changes in osmotic tension which affect the volume of the red cells 
may occur not only in the plasma but also in the red cells. Thus, 
if the red cells in chlorosis are for some developmental anomaly 
deficient in salts they would shrink in plasma of normal (0.9 per 



CHEMISTRY OF THE BLOOD. 89 

ceut.) osmotic tension, wliile normal cells would swell in the watery 
plasma supplied after liypodermoclysis for hemorrhage. 

The isotonic relations of the blood do not apparently depend 
entirely upon the presence of salts, but are affected also by the pres- 
ence of other diffusible principles, as the albumins. Limbeck finds 
only 0.2 per cent, of salts in red cells, yet their isotonic tension is 
equivalent to at least 0.46 per cent. NaCl. 

Hamburger finds that albumins, phosphates, and chlorides behave differ- 
ently under changing osmotic conditions. When a little acid is added to 
blood, albumins and phosphates pass from red cells to serum, while chlorides 
pass from serum to cells, but when alkali is added the opposite transfer is 
induced. Similar physical effects are produced by the passage of oxygen 
and carbonic acid through the blood, and Hamburger suggests that these 
factors take important part in the metabolic exchanges in the capillaries. 

One of the chief physiological relations of the isotonic tension of 
the blood is its influence in confining Hb to the red cells. 

Hamburger, who was one of the first to study this subject, regarded the 
fixation of Hb as the result solely of osmosis on the fluid Hb lying within 
the membrane of the red cell. Yet the opinion of Hoppe-Seyler that Hb 
enters into chemical or molecular union with the stroma of the red cell, and 
the fact that the existence of a membrane about the erythrocyte has not been 
satisfactorily proven (Limbeck) render this belief uncertain. Limbeck offers 
evidence to show that there are other than purely physical influences con- 
cerned with this important function, viz., the chemical union of Hb with other 
elements of the red cells, and the influence of albumins on osmosis. 

Physiological variations in isotonic tension of the blood are numerous. 
That of venous is slightly higher than that of arterial blood (0.02 
per cent.). The addition of CO, CO2, hydrogen, nitrogen, arsenic, 
or a trace of acid increases isotonic tension, while oxygen and traces 
of alkali diminish it (Limbeck). In pathological conditions, from 
a series of fifty-four observations on blood from venesections. 
Limbeck concludes : During acute infections, especially typhoid 
fever, erysipelas, and pneumonia, the isotonic tension of the blood 
is frequently much increased, but not always or constantly so. In 
general disturbances of nutrition the tension of the blood is very 
variable ; in diabetes and osteomalacia it was normal ; in leukemia 
it was much increased ; in jaundice it was low, while in chlorosis 
it was low, and in severe secondary anemia higher than normal. 

In pregnancy and lactation Vicarelli found a distinct increase in osmotic 
tension — i. e., a diminished resistance of the red cells to water (0.6 to 0.66 per 
cent. NaCl). While Limbeck and Castellino found the red cells less resistant 
in typhoid fever, Bianchi and Mariotti found that experimental injections of 
B. typhosus lowered the isotonic tension of the blood, although filtered cul- 
tures of this and other bacteria had the opposite effect. Cavazanni found 
that injections and inunctions of mercury slightly increased the resistance of 
the red cells. 

The tension of the serum has been investigated by Hamburger, 
using another method, who found no change after bleeding. Yiola 
and Jona, during seven hours following venesection, found a moderate 
diminution, while Limbeck, in three portions of blood, taken at 
intervals during the exsanguination of a dog, found nearly constant 



90 GENERAL PHYSIOLOGY AND PATHOLOGY. 

conditions, and Adler found little variation in the tension of the serum 
in various diseases. 

It will thus be seen that the knowledge of this subject is yet in a 
very rudimentary condition, although its importance in hematology 
invites further investigation. 

Alkalescence of the Blood. 

It is an established principle of physiology that the capacity of 
the blood to absorb COg depends on its alkalescence. 

When one compares the results of direct alkalimetry obtained by 
any of the recognized methods with the proportion of COg obtained 
after the dissociation of carbonates by strong acids, marked discrep- 
ancies are observed. The volume of COg differs greatly from the 
degree of alkalinity obtained by direct titration. To explain this 
fact it must be supposed that certain basic properties of the blood 
are brought into action by alkalimetric methods which are not active 
during life, or else that under changing conditions of metabolism the 
blood is required to absorb varying quantities of CO2, which are by 
no means necessarily proportional to the capacity of the blood to 
absorb this element. 

There are g;ood physiological grounds for supposing that both of these con- 
ditions actually exist. It is probable that the existing methods of titration 
are sensible to the alkaline carbonates and phosphates, which are principally 
concerned in the alkalinity of the blood, and, as well, to some acid-neutral- 
izing albuminous principles that are liberated from plasma and red cells 
during alkalimetric procedures (Limbeck and Steindler). To what extent 
the phosphates and albumins are concerned in the physiological functions 
centred in the alkalinity of the blood is not known, but it has seemed to 
the writer that the opponents of the titration method have failed to consider 
the possibility that other important functions besides that of absorbing CO2 
may depend on the alkalinity of the blood {e.g., fibrin formation), and that 
the results of the titration method, therefore, deserve recognition in the study 
of the pathology of the blood. 

On the other hand, the attempt to measure the alkalescence of the blood 
by the volume of CO2 recovered after addition of acids involves a needless 
confusion of the problem, as such estimations include both the CO2 loosely 
combined with Hb and that more firmly united with the alkalies. Yet the 
physiological significance of each of these combinations is probably very 
different, the former representing the respiratory activity of the blood and 
the metabolic activity of the tissues, while the latter is related to other less 
definitely known functions. Moreover, it by no means follows, as has been 
said, that the volume of CO2 recovered from the blood represents the total 
quantity that the blood is capable of absorbing, or is any indication of its 
acid neutralizing power. Bunge calculates that after allowing for the amount 
of sodium required to saturate the only strong mineral acid of the plasma 
(HCl), there is enough sodium left to fix 63 volumes per cent, of CO2 as car- 
bonate and an equal additional amount as bicarbonate, which is far more than 
the amount of CO2 actually present in the blood. 

Again, the attempt to estimate the alkalescence of the blood, considered 
from either the biological or chemical standpoint, by the content in CO2 
involves several probable errors. There may, first, be a diminished produc- 
tion of CO2 in the tissues in pathological conditions. There may be a dimin- 
ished absorption of CO2 by the blood, owing to chemical changes in the tissues 
or mechanical impediments in the circulation. Finally, there may be simple 
absorption of CO2 uncombined with acid neutralizing principles (Schafer). 



CHEMISTRY OF THE BLOOD. 91 

Of the actual existence or importance of these factors, it is, with the present 
knowledge of physiology, difficult to judge, but since they stand as uncertain 
quantities, it seems unwise to rely upon any such indirect method of judging 
of the alkalinity of the blood. 

It would seem, therefore, that both alkalimetry and the estimation of CO2 
furnish important information in regard to the state of the blood, but there 
are no good a 7Jr/ori reasons to suppose that both measure the same property 
of the blood, while the practical results obtained positively disprove such a 
view. When laked blood is titrated a high degree of alkalescence is obtained, 
as this method takes account of all acid-neutralizing principles, carbonates, 
phosphates, and albumins of plasma, and red cells. When serum is titrated, 
the acid neutralizing principles of red cells are ignored, and lower grades of 
alkalinity are obtained. When the CO2 is estimated account is taken only of 
the carbonates, but albumins and phosphates are ignored, and the presence 
of any dissolved CO2 disturbs the computation, while the possibility still 
remains of accidental variations in the ratio between the CO2 actually present 
and total capacity of the blood to absorb this acid. 

Brandenburg distinguishes between the total alkalescence of the blood and 
its ''alkaline tension," the latter signifying the diffusible alkalies, the former 
those in non-diffusible combination with albumins. The percentage of diffu- 
sible alkali increases as the albumins of the blood diminish. In normal blood 
he found about 20 per cent, of the alkali diffusible, in chlorosis about 33 per 
cent. The freezing point of blood was considerably influenced by the diffusible 
alkalies, but very little by those combined with albumin. (See Diabetes.) 

The studies of the CO.^-content of the blood have given the follow- 
ing chief results, as summarized by Limbeck : 

Venous blood is always richer than arterial in CO2, and both are 
subject to minor physiological variations, 33.37 to 45.3 volumes per 
cent. (Schafer, Kraus). 

Febrile processes are generally accompanied by diminution of CO2 in 
the blood, often in proportion to the height of the fever, 34.18 to 20.9 
volumes per cent. (Geppert). This condition, according to Geppert 
and Minkowski, is referable to the abnormal production of acid 
metabolic principles of the blood, a view which is supported by 
Kraus, who, in fevers, along with a diminution of CO2 (10 to 20 
volumes per cent.), found an increase in the acid principles of the 
blood. 

In the cachexia of carcinoma Limbeck and F. Klemperer found 
marked diminution of the COg of the blood (9.67 to 20.5 volumes per 
cent.), but did not estimate the acid principles. Similar results fur- 
nished by other observers indicate that in diabetic coma the blood is 
frequently very deficient in CO2 (Minkowski, Stadelman, Kulz, 
Hallervorden, Kraus). Yet Kraus in one case found a normal 
quantity. A simultaneous increase in acid principles has been 
demonstrated in one case of diabetic coma by Kraus, and on these 
grounds it has been concluded by various authors that in diabetes 
there exists an acid intoxication probably from oxybutyric and 
diacetic acids. Limbeck accepts this view and concludes from the 
various studies that in acute febrile infectious diseases, in cancerous 
cachexia, and in diabetic coma, a diminution in CO2 and an increase 
of acid principles of the blood have been fully demonstrated, pointing 
in all probability to the existence of an acid-intoxication in these 
diseases. In leukemia Kraus^ found a slight deficiency of COo 
(20.29 volumes per cent.). 



92 GENERAL PHYSIOLOGY AND PATHOLOG Y. 

From the direct alkalimetry of the blood or serum much less 
uniform results have been obtained. A fairly constant normal alka- 
linity has been established with titration methods, v. Jaksch^ placed 
the alkalinity of normal blood at 0.26 to 0.30 per cent. NaOH; Kraus, 
at 0.226 per cent. ; Jeffries, at 0.2 per cent. ; Drouin, at 0.206 per 
cent. ; Freudberg, at 0.2 to 0.24 per cent. ; Limbeck, 0.220 to 0.256 
per cent. In laked blood it has been found much higher by Loewy, 
0.449 per cent.; by Berend, 0.45 to 0.5 per cent. Peiper found slightly 
greater alkalinity in the blood of Avomen than in that of children, 
and in the blood of men over that of women. Berend and Preisich, 
using Tausczk's method, found the alkalinity of the blood to be very 
high at birth and for the first six months, after which it diminishes 
rapidly, reaching its lowest point in the second year. After the third 
year it increases until at the sixteenth year it reaches the normal 
degree of adult life. A constantly diminished alkalinity in the blood 
during fevers has been reported by the above authors, by Pumpf, and 
others, and in carcinoma (Pumpf), anemia (v. Jaksch, Peiper), leu- 
kemia (Peiper, Rumpf), uremia, cirrhosis, and osteomalacia (v. Jaksch). 
On the other hand, the results obtained by Loewy and by Limbeck 
and Steindler, using their particular methods, were extremely varia- 
ble, and these variations were about equal in health and disease. 

From the observations of Fodor, Behring, Zagari, Calabrese, 
Cantani and E,igler it has been shown that during infectious diseases 
the alkalinity diminishes as the disease progresses unfavorably, reaches 
its lowest point just before death, and that the alkalinity of the blood 
is essentially connected with the natural or acquired immunity of 
the animal organism against bacterial infection. Fodor found that 
immunization of animals against anthrax, cholera, and swine plague 
increased the alkalinity of the blood. No increase followed injec- 
tions of bacillus typhosus or tuberculosis. Burmin found that the 
alkalescence of the blood in anemia varies directly with the red cells. 

Using his own method Eigler has recently contributed an elaborate study, 
with the following main conclusions : 

The alkalinity of normal rabbit blood does not vary more than 6 per cent. 
After infection by various pathogenic bacteria, including typhosus and tuber- 
culosis, especially if fatal, there is uniform and usually marked diminution 
in the alkalinity of the blood. As recovery from the infection follows the 
alkalinity increases. Similar results followed injections of various bacterial 
toxins, of phosphorus, potassium chlorate, picric acid, biliary acids, pilo- 
carpin, and atropin. 

He found, as did Cantani and Fodor, that injections of diphtheria anti- 
toxin, anthrax vaccine, etc., causes a marked but temporary increase of 
alkalinity. In rabbits treated by injections of serum of various animals 
considerable variations in the alkalinity of the blood were observed. 

In twenty-three patients suffering mostly from infectious diseases Eigler found 
similar variations with those observed in animals. 

The Acidity or Basic Capacity of the Blood. 

There are certain unsaturated salts in the blood, jS'aHCOg, 
[N'aHgPO^, and probably Na2HPO^ (Limbeck), which although alka- 
line to litmus are acid to phenolphthalein, and are capable of uniting 



CHEJIISTEY OF THE BLOOD. 93 

with bases. While fresh blood is alkaline, serum reacts as acid to 
pheuolphthalein. The capacity of the blood salts to neutralize bases 
has been called its basic capacity by Kraus,^ who devised a delicate 
and somewhat difficult method of measuring this capacity. 

In normal venous blood Kraus found a basic capacity of 0.162 
to 0.232 per cent. NaOH, which increased in febrile conditions to 
0.209 to 0.272 per cent. NaOH. His demonstration of a marked 
increase of basic capacity (0.347 per cent.) in diabetes has been 
regarded as strong evidence of an acid intoxication in this disease. 

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Geppert. Zeit. f. khn. Med., Bd. 2, p. 364. 



94 GENERAL PHYSIOLOG Y AND PATHOLOGY. 

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Glogner. Virchow's Archiv, Bd. 126. 

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Halpern. Berl. kl. Woch., 1902, p. 1121. 

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f. Phys., Bd. 9, No. 6. 

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p. 1018. Zeit. f. klin. Med., Bd. 20. 

Hanriot. Compt. Rend. Soc. Biol., 1896, p. 925. 

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Hoffman. Arch. f. exper. Path., Bd. 16, p. 133. 

Hoppe-Seyler. Physiol. Chemie, 1881. 

Hougouneng. Maly's Jahresber., 1888, XVII., p. 430. 

Huppert. Zeit. f. phys. Chem., Bd. 15, pp. 335, 546. 

V. Jaksch. ' Zeit. f. khn. Med., Bd. 24, p. 429. ^ ibid., Bd. 23, p. 187. ' Zeit. f. 
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Jellinek. Wien. klin. Woch., 1897, No. 47. 

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F. Klemperer. Charite Annalen, Bd. 15, p. 151. 

Klemperer. ^ Deut. med. Woch., 1895, No. 40. 

Kossel. Zeit. f. physiol. Chem., Bd. 22, p. 74. 

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Arch. f. exper. Path., Bd. 26. 

Kulz. Zeit. f. Biol., Bd. 20, p. 165. 

Lepine. Lyon Med., 1890, No. 3. 

Lepine, Barral. Compt. Rend. Soc. Biol., 1891. 

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Lilienfeld. ^ Zeit. f . Phys. Chem., Bd. 18, 473. ' Ibid., Bd. 20, p. 155. 

Lillie. Amer. Jour, of Physiol., vol. 7, p. 412. 

Limbeck, Pick. Prag. med. Woch., 1893, Nos. 12-14. 

Limbeck, Steindler. Cent. f. inn. Med., 1895, No. 27. 

Livierato. Arch. f. klin. Med., Bd. 53, p. 303. 

Lloyd Jones. Jour, of Physiol., vol. 8, p. 1. 

Locke. Bost. Med. and Surg. Jour., vol. 147, p. 289. 

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p. 785. 

Lowit. Studien u. Phvs. u. Path. d. Blutes, Jena, 1892 

Ludwig. Wien. med. Woch., 1881, p. 122. 

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Maragliano. XL Cong. inn. Med., 1892. Berl. klin. Woch., 1892, No. 3L 

Matthes. Berl. klin. Woch., 1894, Nos. 23, 24. 

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CHEJIISTBY OF THE BLOOD. 95 

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Zagari. Giom. inter, della sci. med., 1892. 



CHAPTER III. 

MORPHOLOGY AND PHYSIOLOGY OF THE RED CELLS. 

In fresh normal blood the red cells appear as homogeneous bicon- 
cave disk-shaped bodies, with opaque yellowish rims and nearly trans- 
parent centres. In the capillary circulation they exhibit remarkable 
elasticity, folding, indenting, and greatly elongating, without rupture. 
After early infancy they are invariably non-nacleated. They show 
a strong tendency to cohere to one another by their flat surfaces, 
forming long rows (rouleaux). This property has been referred to 
the presence of a fatty material surrounding the red cells. 

Brunton placed cork disks covered with soap in acidulated water, and found 
that they formed rouleaux, probably with the liberation of fatty acids. Rou- 
leaux formation by red cells, he suggests, is probably due to the liberation of 
fatty acids under the influence of COg. Peskind has shown that agglutination 
of red cells is produced by various acids and acid salts through alteration in 
the alkalinity, and combination with the nucleoproteid, of the cell envelope. 

In dry specimens when thinly spread and rapidly dried the cells are 
circular in outline, their concavities are obliterated, and they stain 
evenly throughout. When rather thickly spread the rouleaux are 
retained, the concavities persist, and the centres may be nearly trans- 
parent while the thicker rims are densely stained. 

Neither membrane nor retlGuhmi have been fully demonstrated in 
the human red blood cells, although both, from analogy, have been 
supposed to exist. It is more probable that the hemoglobin is held 
in compact form principally by a chemical union with other albu- 
minous constituents of the cell (Schafer). 

Peskind's studies indicate that the red cells are enveloped by a 
hemoglobin-free layer composed of lecithin, cholesterin, and a nucleo- 
proteid. 

Staining Reactions. The living red cell is achromatic, but 
when fixed is markedly acidophile in quality, a property probably 
residing exclusively in the Hb. In the centre of the cell there 
is an achromatic constituent which fails to stain with acid dyes, but 
under some circumstances this central substance may become partially 
separated or even extruded from the cell, when it stains lightly with 
methylene blue, and yields the specific reaction of chromatin (Nocht's 
method). 

Two views regarding the structure of the red blood cell have been main- 
tained. According to the tirst, the red blood cell is vesicular, consisting of 
colored semifluid contents, hemoglobin, surrounded by a membrane and sup- 
ported by a stroma composed of various substances, principally lecithin, 
cholesterin, and cell-globulin (Schafer). According to the second view, 
the red cell is not vesicular, but a viscous solid mass, consisting of a colorless 



PLATE I. 









'• • 




:.^** 



^^S^ 




Normal Blood. (Triacid Stain. 



Fig. 1. Normal red cell, flatly spread, and evenly stained. 

Fig. 2. Normal rouleau. 

Fig. 3. Normal red cells, var^dng slightly in size, thickly spread, showing central 

clear area. 

Fig. 4. Normal red cell, of shghtly altered shape. 

Fig. 5. L^rmphocyte, medium size. 

Fig. 6. Large mononuclear leucoc^^e, incvirved nucleus. 

Fig. 7. Polynuclear neutrophile leucoc^^e. 

Fig. 8. Eosinophile leucocyte. Separate nuclear lobes. 



MOBPHOLOGY AND PHYSIOLOGY OF BED CELLS. 97 

elastic stroma which is condensed at the periphery and which supports, partly 
by mechanical means and partly by chemical union, the hemoglobin and other 
constituents of the cell (Rollet, Brucke). 

It is not impossible to partly reconcile these opposing views regarding the 
peripheral condensation of stroma as in many respects similar to a membrane. 
That the cell is not strictly vesicular with separable fluid contents is shown by 
the fact that it may be subdivided without escape of contents, each fragment 
assuming the discoidal shape. 

According to Foathe hemoglobin is limited to a peripheral layer of granules 
under which lies homogeneous cell protoplasm, and this view is supported by 
the occasional escape in pathological conditions of a central achromatic sub- 
stance, leaving the hemoglobin more or less intact. 

Size of Red Cells. In normal subjects the average diameter of 
red cells varies between 7/1 and Sjut, depending considerably npon the 
method employed in preparing the specimen. The following table, 
compiled by Limbeck, shows the results obtained by different writers : 

Limits. Average. 

Welcker 4.5-9.5," 7.2-8.1/^ 

Valentin 7.0 

Malinin . . 7.7 

Hayem 6.0-8.8 7.5 

Malassez 7.6 

Laache 6.0-9.0 8.5 

Bizzozero 7.0-7.15 

Gram 6.7-9.3 7.7-8.0 

From 75 to 90 per cent, of the cells fall within average diameters. 
Sex has no influence upon the size of red cells, and after infancy the 
diameters remain constant. In normal infant's blood the variations 
in the size of the cells are considerable, 3.3// to 10.3// (Hayem). 

In pathological conditions variations in the size of red cells are one 
of the most important of morphological features. In general, varia- 
tions in the size of the cells indicate a severe and chronic anemia,, 
while in mild and in very acute anemias the diameters are usually 
little altered. 

Anisocytosis is a term used to indicate variations in the size of red 
cells without the deforming changes in shape involved in poikilo- 
cytosis. 

Microcytes are cells distinctly under the normal size, and may show 
a diameter of 4// to 1//. 

Several influences appear to be concerned in the formation of 
microcytes. It is probable that cells poor in Hb, lying in plasma of 
high gravity and osmotic tension, may be reduced in size from the 
direct loss of substance and the concentrating influence of a fluid of 
high osmotic tension. Many microcytes probably result from the 
splitting of portions of degenerating and ameboid red cells, as in 
pernicious anemia. The occasional occurrence of nucleated red cells 
of small or minute size indicates that some microcytes arise by 
division of undersized mother-cells. This mode of origin is probably 
limited to pernicious anemia. 

The clinical significance of the presence of undersized cells or dis- 
tinct microcytes is rather indefinite. In some cases of chlorosis the 
cells appear to be uniformly smaller than normal, but this character 

7 



98 GENERAL PHYSIOLOGY AND PATHOLOGY. 

is not invariable. In some cases of chronic anemia of pernicious 
grade tlie majority of cells are undersized and deficient in Hb. In 
primary pernicious anemia microcytes with increased or diminished 
Hb are constantly present. Tallquist believes that the presence of 
many microcytes is an indication of rapid destruction of blood. 

Megalocytes are cells distinctly larger than normal. They usually 
vary between 10// and 20/i in diameter. Most of these cells form 
from the division of the large nucleated red cells which appear in 
red marrow in severe chronic and especially in pernicious anemia. 
In addition to this mode of origin it is probable that many slightly 
enlarged cells and megalocytes are produced by the swelling which, 
under the laws of osmosis, results when red cells lie in plasma of 
low gravity and low osmotic tension. Megalocytes may show an 
excess or a deficiency of Hb, and frequently exhibit a brownish 
stain after eosin. 

The presence of megalocytes indicates an anemia of severe grade 
and usually of rather long standing. Their appearance denotes 
regenerative activity on the part of the blood (Tallquist). Some 
authorities arbitrarily suggest that vv'hen megalocytes form more 
than 10 per cent, of the cells the case should be classed as pernicious 
anemia. In secondary pernicious anemia the megalocytes are fre- 
quently deficient in Hb, while in primary pernicious anemia they 
usually contain an excess of this principle. 

Nucleated Red Blood Cells. While the presence of nucleated 
red cells in the blood at any period of extra-uterine life may be con- 
sidered pathological, it must be admitted that prolonged search in 
the blood of infants shortly after birth Avill usually disclose the 
presence of a few of these cells. 

Normoblasts are nucleated red cells of normal size and character 
(7// to 9/i). They usually show a normal or slightly increased quan- 
tity of hemoglobin, fail to show a biconcave form, do not cohere 
in rouleaux, and exhibit central densely staining spheroidal nuclei 
occupying one-third of the diameter of the cell. Much less fre- 
quently the nucleus is subdivided into two or three lobes, more or 
less closely connected, while mitotic figures in normoblasts have 
several times been described (Luzet, Troje, Askanazy^). 

Normoblasts are most commonly seen, in very variable numbers, 
in the milder forms of anemia, chlorosis, acute anemia from hemor- 
rhage, early leukemia, etc. They may be very abundant in the 
anemia of children, especially in v. Jaksch's type. In severe anemia 
they are usually associated with larger nucleated red cells. In chil- 
dren any severe disturbance of the circulation, especially if accom- 
panied by affection of the bone-marrow, may cause the appearance 
in the blood of a few normoblasts. Severe leucocytosis in children 
and even in adults may draw a few normoblasts into the circulation. 
In anemic subjects antemortem leucocytosis may be of this character. 
In chlorosis a periodical increase of normoblasts, lasting four to six 
days, repeated at intervals, apparently favored by rest in bed and 
successful medication, and accompanied by a marked increase in red 
cells, has been described by v. Noorden under the term ^^ blood 



MOBPHOL G Y AXB PH YSIOL OGY OF BED CELLS. 9 9 

crisis/' This phenomenon chiefly has given rise to the belief that 
the appearance of normoblasts is of favorable import in anemia. 
This opinion may be accepted^ not becanse the normoblasts appear 
in the circulation, but because their appearance indicates active 
reproduction and discharge of red disks from the marrow, and 
demonstrates that the type of blood formation is physiological. 

Megaloblasts are nucleated red cells of larger than normal dimen- 
sions (10« to 20«). When exceeding 20/i in diameter, they are usually 
called giganiohlasts. They are usually circular in outline, but are 
readily deformed in spreading. Megaloblasts may show a deficiency 
of hemoglobin, but usually contain an excess, in which case they are 
apt to stain brownish with eosin (polychromatophilia). The nuclei 
of megaloblasts show a great variety of forms. They may be found 
in : (1) the ordinary vesicular form of the resting stage, with intra- 
nuclear network and nodal thickeniugs, but without nucleoli ; or they 
may be {2) pyhiomorphous, consisting of one or several densely stain- 
ing lobes, either distinctly separate or grouped in irregular rosette 
form ; or (3) they may exhibit phases of normal or pathological 
mitosis, with irregular wreaths or two or three unequal asters ; or 
(4) they may show many stages of karyorrhexis, with fragmentation, 
vacuolation, fading of segments of nuclei, as well as minute sub- 
division into fine basic staining particles widely scattered in the cell. 
(See Plate YI.) 

The significance of the presence of megaloblasts in the blood depends 
on the conditions with which they are associated. 

Megaloblasts are seen in smears of the marrow of many young 
infants, and when seen in the circulation of such subjects in small 
numbers and with a majority of small nucleated cells, they have the 
same significance as normoblasts. In cases of severe anemia of 
adults a few nucleated red cells of moderately large dimensions are 
sometimes seen with a larger number of normoblasts, when no special 
significance can be attached to their discovery. 

When the majority of a considerable number of nucleated red cells 
are megaloblasts, especially if gigantoblasts are present and unequal 
mitotic figures are observed, the diagnosis of primary pernicious 
anemia is justified. The presence of a few megaloblasts alone is 
usually found only in primary pernicious anemia, but may occur in 
pernicious secondary anemia. Possibly the discovery of a single 
gigantoblast may warrant the diagnosis of primary pernicious anemia. 

In general, the appearance of megaloblasts in the blood indicates 
that a pathological type of blood formation has been established in 
at least a part of the red marrow. Whether this change represents 
a reversion to the embryonal type of blood formation, as suggested 
by Cohnheim, cannot yet be determined, and will be considered 
later. Probably the low osmotic tension of the watery plasma may 
be responsible for some of the increased size of the nucleated red 
cells of pernicious anemia. 



L.ofC. 



100 GENERAL PHY8I0L0G Y AND PATHOLOG Y. 



Pathological Changes in Red Blood Cells. 

Simple loss of Hb is one of the commonest changes occurring in 
red cells, this being the chief cellular lesion in chlorosis and mild 
secondary anemia. When deficient in Hb the cell exhibits an 
enlarged central area of variable outline. In extreme cases the cell 
may be reduced to a very thin ring of Hb, inclosing a wide and 
perfectly transparent central area. In dry specimens, such cells 
when thinly spread and rapidly dried may fail to exhibit a marked 
central clear area, but the whole cell shows a uniform pallor. Occa- 
sionally the central clear area is irregular, owing either to ameboid 
changes in the red cell or to the unequal loss of Hb in different 
parts of the cell, or, frequently, to artificial influences. Thus may 
arise minute clefts and the heaping of remnants of Hb in the centre 
of the cell. (See Plate VII.) 

Poikilocytosis is a term applied to the appearance in blood of mis- 
shapen red cells. Probably the chief mode of origin of poikilocytes 
is through the effects of ameboid motion of a portion or the whole 
of a cell, which is one of the phenomena occurring in degenerating 
red cells. A great variety of shrunken and misshapen cells are 
produced artificially in dried specimens of anemic blood. The true 
poikilocyte is usually a pear-shaped cell with a short globular pro- 
jection at one or more poles. Extremely irregular cells usually result 
from shrinkage or trauma. Very small cells may be formed by the 
separation of fragments of poikilocytes (Ehrlich). 

Poikilocytosis is an indication of a severe anemia with degenerative 
changes in the red cells. 

Ameboid motion of entire cells or of fragments of cells, or of cen- 
tral colorless masses in necrobiotic cells, may be observed, in slight 
degree, in many severe anemias. This phenomenon, which is more 
commonly observed in the blood of the low vertebrates, is probably 
responsible for the production of many poikilocytes and for the sub- 
division of red cells, but is otherwise lacking in special significance 
(cf. Askanazy). 

Variations in size of red cells is an important feature of degenera- 
tive processes which is considered elsewhere (p. 97). 

In cases of acute poisoning in man and animals, a considerable 
variety of degenerative changes in red cells has been described by 
many writers, but these do not yet admit of accurate classification. 
Among them may be mentioned : (1) the hemoglobinemic degener- 
ation of Ehrlich, which consists in the appearance of droplets of Hb 
within the cell ; (2) the subdivision of the cell with formation of 
microcytes, as seen in some forms of poisoning (Litten) and after 
severe burns ; (3) the specific reaction of diabetic blood described by 
Bremer ; and (4) the changes in color to be noted after poisoning by 
hydrochloric acid, hydrocyanic acid, chlorate of potash, and some 
coal-tar products. 

The malarial j^ci^'osite produces a peculiar series of degenerative 
changes in the red cell which will be considered later. 



MORPHOLOGY AXD PHYSIOLOGY OF RED CELLS. 101 

Anemic or Polychromatophilic Degeneration. Polychromasia. 
Polychromatophilia. Under the term polychromatophilia two 
apparently distinct conditions have been described. 

The term is applied by Ehrlich' to the appearance, especially in 
cases of chronic anemia, of cells which, after hematoxylon and eosin, 
instead of staining light red take a bluish red or violet tinge, or, in ex- 
treme examples, even take a deep blue stain. These various abnormal 
tints are referred by INIaragliano, Castellino, and Ehrlich, to a progres- 
sive coagulation-necrosis of the cell which thereby loses its power to 
retain Hb, and, gradually yielding this element to the plasma, loses also 
its normal affinity for acid dyes. This opinion is based on the follow- 
ing grounds : (1) the appearance of cells showing an advanced stage 
of the change, in which the frequent breaks in contour ^^ convince 
every practised eye that the cell is approaching solution ;" (2) by 
the abundance of such cells in starving animals where new formation 
of red cells is not to be expected ; (3) by their abundant presence 
within twenty-three hours after hemorrhage, when normoblasts are 
only exceptionally seen ; and (4) by the constant polychromatophilic 
tendency of megaloblasts as compared with normoblasts. 

Gabritschewsky, Smith, Askanazy,^ Engel, Dunin, and many 
others, believe that polychromatophilic disks are not degenerating, 
but, on the contrary, are the youngest red cells of the blood. This view 
is supported by the abundance of such cells shortly after severe 
hemorrhages and in many other conditions where red cells are being 
rapidly formed. Askanazy found polychromatophilia of all the 
nucleated red cells in the marrow of a rib just after its excision and 
before degenerative changes could have set in, and states that a large 
proportion of cells in the liver of the seven months' fetus are poly- 
chromatophilic. Walker also found as high as 34.75 per cent, of 
basophilous red cells in the blood of a fetal puppy, while in the 
marrow of various healthy domestic animals they varied from 1 2 
to 62 per cent. 

Engel has shov/n that there is a physiological polychromasia 
belonging to a portion of the red cells of the embryo, and Ehrlich^ 
accepts this fact without yielding his opinion that, in the adult, 
polychromasia is a sign of degeneration. According to Engel, poly- 
chromatic cells appear when rapid new formation of red corpuscles 
is demanded and when there is not time for the complete shrinkage 
of nucleus and development of orthochromatic cells. 

The bearing of the first studies of Maragliano and Castellino is 
here of importance. These observers found that normal blood in 
carefully prepared fresh specimens begins to show distinct alterations 
of the red cells after standing ten to twelve hours. These consist in 
widening of the central colorless area, appearance of ameboid activity 
in this area, formation of poikilocytes and development of a basic 
staining quality in a part or the whole of the cell. In various patho- 
logical conditions they found these changes present immediately 
after shedding, and the more rapid their appearance the graver was 
the general condition of the patient. The authors believe that these 
changes may occur in the circulating blood ; that they are referable 



102 G-ENEBAL PHYSIOLOGY AND PATHOLOGY. 

to decreased stability of cells and increased globulicidal activity of 
plasma; and that they afford valuable clinical evidence of destruc- 
tion of blood. They depict cells which show the polychromatophilic 
tendency of Ehrlich, and other cells in lohich there is the formation of 
a centi^al mass ivhich stains bluish by methylene blue^ and which has 
been shown to herald the extrusion of a portion of the red cell in 
the form of blood plates. (See Plate 11., Fig. 2.) 

The processes represented by these two kinds of altered cells may 
be related, but are certainly not identical, and since the chief evidence 
in favor of the degenerative nature of Ehrlich's polychromatophilic 
cells is found in the studies of Maragliano, it would seem that further 
investigation is necessary before one can accept the view that such 
cells are necrotic. 

Finally, it should be mentioned that Sherrington refers the 
brownish staining reaction frequently seen in red cells in severe anemia 
to incomplete oxidation of Hb. 

To summarize the evidence in this field it appears that two dif- 
ferent changes in red cells have been included by different authors 
under the term polychromasia : (1) A diffuse brownish or poly- 
chromatic staining tendency in red cells (polychromasia of Gabrit- 
schewsky — Plate YIL, Fig. 5) occurs in various forms of anemia, 
abundantly in normal marrow, and especially in fetal blood and 
marrow It is probably referable to simple deficiency in quantity 
or change in quality of hemoglobin, and, while not essentially a 
degenerative process, is frequently seen in combination with granular 
degeneration of the red cells, with which its significance must then 
be regarded as identical. (2) The appearance in red cells of large 
or small basic staining areas (polychromasia of Maragliano- — Plate 
YI., Fig. 6) occurs in severe anemia and toxemia, has no relation 
to the other type of polychromasia, but is related to the granular 
degeneration of Grawitz. It is an evidence of degeneration of the 
red cells. 

Granular Degeneration of Red Cells. Punctate Basophilia of 
Red Cells. The attention of pathologists has long been attracted 
by the presence of bluish staining granules and masses in red cells, 
and they have repeatedly been interpreted as remnants of a nucleus. 
In specimens stained by the Xocht-Romanowsky method these 
masses usually give the reaction of chromatin. Lately the formation 
and significance of these bodies have been fully considered by ]\Iaxi- 
mow, who calls them " nucleoids ^^ and whose conclusions regarding 
their nuclear character can hardly be doubted. 

In 1893 Askanazy^ described the appearance of many fine baso- 
philic granules in the bodies of nucleated red cells in pernicious 
anemia, regarding them as evidence of karyorrhexis. In 1894 
Schumann saw such cells in the anemia of bothriocephalus, and in 
1896 Lazarus described them in twenty cases of pernicious anemia, 
while failing to find them in other diseases. Later they were 

* Ehrlich warns against the use of methylene blue in demonstrating polychromatophilia, using 
only the triacid mixture, or hematoxylon and eosin (Die Anemie, p. 34). 



JIOBPHOLOGY AXD PHYSIOLOGY OF BED CELLS. 103 

described in pernicioas anemia and varionsly interpreted by Klein, 
Zenoni/ Lenoble, and Grawitz/ Very similar changes have been 
described in secondary anemia, normal blood, in bird's blood, and 
in that of the human embryo by Askanazy, Gabritschewsky, Klein, 
Pappenheim, and Engel.^ Plehn found them abundantly in the blood 
of malarious subjects and regarded them as remnants of the parasite. 

Grawitz has recently described the appearance and studied the 
nature and occurrence of such cells in human blood, concluding that 
they represent a specific form of degeneration. He did not find any 
evidence of increased karyolysis in the normoblasts of marrow Avhen 
degenerating cells were found in the blood, except in very severe 
anemia. The exact origin of the bluish staining granules he is 
unable to explain, but thinks they have no connection with a process 
of karyolysis. In pernicious anemia and leukemia Grawitz could 
always find many cells in granular degeneration, but in eleven cases 
of severe chlorosis they were missing. In carcinoma they were 
present when the tumor was in such a situation ^* as to favor the 
absorption of toxic substances.'' Thus they were present in ten 
cases of gastric and esophageal cancer, but absent in two cases of 
uterine carcinoma. They were not found in numerous cases of 
tuberculosis and syphilis. In lead poisoning they have been found 
very abundantly, and often before any subjective symptoms can be 
detected, by Grawitz, Behrendt, Sabrazes, White and Pepper, and 
others. 

Bloch noted that they are sometimes entirely wanting in fatal 
pernicious anemia, and he found none in a fatal case of hemophilia. 
They were more abundant in his cases of carcinoma than in sarcoma, 
and were absent in cirrhosis and pseudoleukemia, and in one of 
three cases of plumbism. Burckhardt also saw several cases of lead 
colic without degenerating red cells. Lowenthal produced them by 
injection of salts of tin, and they have been seen to result from the 
action of copper, potassium chlorate, mercuric bichloride, pyrodin, 
and phenylhydrazin. Stengel, White, and Pepper found them in a 
great variety of anemias and toxemias, but invariably only in lead 
poisoning. They demonstrated the granules in the fresh blood by 
injecting methylene blue into the jugular vein of a leaded dog. 

The writer has frequently noted these changes in red cells in per- 
nicious anemia, and is convinced that in megaloblasts they often 
result from karyorrhexis, having seen many transitional stages of the 
fragmentation and fine subdivision of these nuclei. In the hydremic 
blood of malarial cachexia they are extremely common. In some 
cases, after overstaining in methylene blue, nearly every red cell 
shows such bluish points, sometimes connected with fine threads. 

The origin and significance of these basic staining granules in red cells has 
been the subject of much controversy. 

Ullman regards them as artefacts, and while this view cannot be accepted 
for all cases their variability in plumbism and other conditions, and the capri- 
cious behavior of the red cells in hydremic blood suggests that great care in 
fixation and staining is demanded in their study. 

Some observations favor the belief that granular degeneration is a character 
exhibited principally by immature red cells, and does not necessarily repre- 



104 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 

sent a regressive progress. Blocli found them very commonly in polychro- 
matic cells, and abundantly in the red cells of fetal mice when the mother's 
red cells were normal. They occur abundantly in healthy animals after hem- 
orrhage, and in disease marked by increased red-cell formation (Jawein). 

Grawitz especially, and many others, maintain the origin from a regressive 
and degenerative process affecting previously normal red cells. 

The exact nature of the change is also disputed. The majority of observers 
believe that the granules are reappearing particles of the diffuse nuclear con- 
stituent of the red cell. 

Grawitz and Bloch deny that they have any relation to karyolysis or to nuclear 
elements, but hold that they represent a precipitate of the dissolved albu- 
minous constituent of the cell. Grawitz distinguishes rightly between the 
large fragments of nuclei seen in karyorrhexis of megaloblasts and the fine 
granules which are found in the true degenerative process, and disposes of the 
theory that the granules always result from karyorrhexis of the nucleus in the 
normoblastic stage. Bloch and Lazarus have seen granular degeneration of 
the protoplasm of mitotic megaloblasts. It is further argued by Bloch that the 
granules cannot be nucleinic acid because they show no selective affinity for 
methyl green, and stain blue with Nocht's method, which colors chromatin 
red. Against these considerations must be urged the fact that the red cell 
contains diffuse nuclear material from which the granules may arise apart 
from karyorrhexis, as Maximow has clearly demonstrated, and that Nocht's 
stain leaves some nuclear elements blue and others red, and may be made to 
stain these particular granules deep red, as in the blood plates. 

The Numbers of Red Blood Cells. It is hardly necessary to 
poiat out that the present method of enumerating the red cells in a 
unit of volume of blood gives an imperfect estimate of their total 
number in the body. Yet the conclusions that are constantly being 
drawn from such information could be justified only in case there 
was a uniform relation between the number of cells per cubic milli- 
metre and their total number in the body. The considerations men- 
tioned in the Introductory Section show that in pathological condi- 
tions no such relation uniformly exists. On the other hand, since 
the total quantity of blood in healthy subjects is properly adapted to 
each individual, the bulk is of less practical importance than the 
proportion in the unit of volume, and the enumeration of red cells 
in tolerably healthy cases, therefore, warrants the same conclusions 
that could be drawn from the estimation of their total numbers in 
the body. 

The original estimates of Welcker (1854), that in the cubic milli- 
metre of blood there are normally 5,000,000 red cells in men and 
4,500,000 in women, have not been seriously disturbed by many 
subsequent observations by means of Malassez's method. Perhaps 
the chief contribution of later observers using Thoma's instrument 
has been the proof that the numbers are more apt to exceed rather 
than fall below these averages, especially in men, a fact that has 
become more certain from the more careful estimates of the last 
decade. Thus the average obtained by Helling was 5,910,000 ; by 
Frederickson, 5,072,000; Zaslein, 5,010,000; Neubert, 5,603,000; 
Graber, 5,081,000; Stierlin, 5,752,000; Reinicke, 5,209,667; 
Andriezen, 6,000,000 ; Hayem, 5,500,000. 

The variations in the number of red cells referable to physiological 
and accidental causes are so numerous and distinct as to require 
their consideration in detail. 



MOBPHOLOGY AND PHYSIOLOGY OF BED CELLS. 105 

1. Time of Day. The variations found by some observers at dif- 
ferent hours of the day may probably, as Limbeck suggests, be re- 
ferred to the influence of digestion and exercise. Reinert found a 
tendency toward diminution of red cells and increase of leucocytes 
as the day progressed with healthy subjects. 

2. Digestion. With but few reports to the contrary, the observa- 
tions of Tierordt and Duperie, Reinert, and Limbeck indicate that 
within one-half to one hour after the ingestion of a full meal the 
proportion of red cells begins to diminish, falling usually 250,000 
to 750,000 per cubic mm. The numbers diminish for two to four 
hours, and then gradually approach the normal. The percentage of 
Hb falls proportionately. These effects are more prominent after a 
largely fluid meal, and are probably referable to the absorption of 
fluids with dilution of the blood. 

For the same reasons hanger has been found by many observers 
to cause in animals a considerable increase in red cells (Bidder and 
Schmidt, A'oit, Subotin, Panum, Groll, Hosslin, Raum). 

The observations on man by Raum, Senator, Luciani, and Grawitz,^ 
do not, however, show that such an increase is either constant or 
invariable in fasting men. Twenty-four hours' fasting usually suffices 
to raise the red cells of dogs 400,000 to 500,000, and in captivity 
they may emaciate from starvation, while the red cells continue above 
normal (Hosslin) ; but in man there has been a lack of uniformity 
in the changes observed. Senator and Luciani finding an irregular 
increase in the number of red cells in the professional fasters Cetti 
and Lucci, while Raum and Grawitz^ found a distinctly anemic con- 
dition established in healthy fasting men. 

3. Sex. The relative anemia of women is not found until men- 
struation is established at about the fourteenth to sixteenth years. 
Indeed, Stierlin, who examined the blood of ten boys and ten girls 
under fifteen years, found a slight and rather uniform difference in 
both red cells (350,000) and Hb (2.5 per cent.) in favor of female 
children. 

While the figures of Welcker, 500,000, have been generally 
accepted as representing the difference between the blood of men and 
that of women, Leichtenstern, from 191 observations, placed this 
difference at about 1,000,000 cells. Later reports (Ziegler, Stier- 
lin), as well as common clinical experience, would seem to indicate 
that the difference does not usually amount to 500,000, and that 
when the number falls below 4,500,000 in women there is some dis- 
tinctly pathological condition to account for the relative anemia. 
There are at hand no systematic comparisons of the number of red 
cells in women at different ages, apart from the immediate effects of 
menstruation and pregnancy. Stierlin has shown that both red cells 
and Hb are subject to more extensive physiological variations in 
women than in men. In specific gravity Dieballa found that with 
the same red cells and Hb the blood of women averages 0.0025 less 
than that of men. 

Menstruation. Since a hemorrhage which removes less than one- 
fiftieth to one-twentieth of the total volume of blood fails to notice- 



106 GENERAL PHYSIOLOGY AND PATHOLOGY. 

ably affect the blood (Vierorclt), the menstrual flow, normally about 
100 to 200 c.c. and extending over a period of some days, usually 
fails to reduce the red cells. On the contrary, both red cells and 
Hb have frequently been found slightly increased after normal men- 
struation (Vierordt, Hayem, Duperie, Scherpf, Reinlj Reinert). This 
result has been referred to stimulation of blood-forming organs. A 
slight leucocytosis has also been noted by Hayem, Moleschott, and 
Eeinert. The clinical rule that normal menstruation in healthy sub- 
jects fails to induce anemia but may do so when associated with 
other causes of anemia, is borne out by Reinert's observations on a 
chlorotic girl. In this patient a moderate flow re-established through 
the use of iron failed to lower the blood count, but at two succeeding 
periods more profuse discharge was followed by a reduction in seven 
days of 700,000 cells. The changes which occur under the most 
favorable circumstances are probably illustrated by the results of 
Sfameni, who examined the blood of six healthy women before, during, 
and after menstruation. He found that normal menstruation reduces 
the Hb 4 to 15 per cent, and the red cells 220,543. During the 
menstrual period the leucocytes are usually slightly increased, average 
330, and the decrease of red cells is less marked (122,443). In the 
intermenstrual period the red cells slowly increase, reaching a maxi- 
mum three days before the succeeding flow. 

In spite of the above largely negative results, it can hardly be 
doubted that a slightly disordered menstruation is a most important 
factor in the etiology of chlorosis. 

Pregnancy. After passing through many phases of conjecture, 
opinions regarding the condition of the blood in pregnancy are now 
based on numerous observations extended and summarized by 
Schroeder, which show" that pregnancy in itself has little influence on 
the Hb or red cells of the blood, and that if anemia exists it is to be 
referred to unhygienic conditions. Postpartum anemia should not 
continue longer than ten to fourteen days, and may be succeeded by 
a slight increase of red cells above the normal. 



PLETHORA. POLYCYTHEMIA. 

It has already been shown that there are good grounds for accepting 
the old belief that there are considerable physiological and pathologi- 
cal variations in the total quantity of blood in the body, and it remains 
to consider here those factors which directly affect the proportion of 
red cells. 

Polycythemia may arise either from an increase in the number of 
red cells or from a decrease in the volume of the plasma. Practically 
it can hardly be said that a true polycythemia from the first-named 
cause is ever observed, as the blood-forming organs are never known 
to produce an excess of red cells, and the effects of transfusion of 
blood are very transitory. Polycythemia from decrease in the 
volume of plasma, however, is very frequently encountered, and 
among its causes may be mentioned diarrhea, dysentery, cholera 



MORPHOLOGY AND PHYSIOLOGY OF BED CELLS. 107 

(Schmidt, Hayem), or any disease attended with excessiv^e watery 
exudate ; conditions marked by insufficient aeration of the blood and 
venous stasis, as endocarditis, emphysema, asphyxia, and in the 
peculiar permanent polycythemia observed at high altitudes ; the 
administration in therapeutic or poisonous doses of various drugs, 
lymphagogues (Grawitz^), phosphorus (v. Jaksch), pilocarpin, eserin, 
etc. (Hamburger), and cold baths. Various other influences lead- 
ing to local polycythemia have been mentioned in the Introductory 
Section. 

The danger of overlooking the true cause of polycythemia is well 
illustrated in Timofjewsky^s experiments, when after the intravenous 
injection of pus an increase of red cells of 1,500,000 to 2,000,000 
was found to result from concealed exudates from mucous and serous 
membranes. 

The Polycythemia of the Newborn. The marked relative poly- 
cythemia of the blood of newborn infants has been constantly attested. 
The following averages have been observed : 

Hayem 5,368,000 

Sorensen 5,665,000 

otto 6,165,000 

Helot 5,531,000 

SchilF 5,825,000 

Bidone 6,500,000 

While the averages of considerable numbers of cases reported by 
the above authors are rather uniform, very marked variations have 
been noted, referable to changes at different periods of the day, 
and to individual peculiarities. Hayem and Helot found that too 
early ligature of the cord might cause a reduction of 500,000 to 
1,000,000 cells. During the first weeks the polycythemia, which is 
usually highest before the first nursing, gradually disappears at the 
rate of about 250,000 cells weekly, but while the average fall of a 
considerable number of cases is very regular, there are marked 
daily variations in individuals of from 500,000 to 1,000,000 cells 
(Schiff). No definite relation between the changes in body weight 
and the number of red cells has been traced, but a marked reduction 
usually follows each nursing. 

The cause of the polycythemia of the newborn is doubtless to be 
found in a temporary concentration of the blood in which a number 
of factors are concerned. The loss of water during the first hours of 
respiration has been regarded as an important influence (Preyer), but 
can hardly account for the condition of the blood in the first hours 
after^ birth. The writer finds that the polycythemia bears a rather 
close relation to the degree of cyanosis exhibited by the expressed 
blood drop, and believes that the concentration of blood is principally 
referable to a state of relative stasis which is then established in the 
peripheral capillaries. 

The Polycythemia of High Altitudes. The observations of 
Bert in 1882 that the blood of animals from the Bolivian plateaus 
showed much increased capacity to absorb oxygen, led Viault to 
examine his own blood while sojourning in the Andes and to find 



108 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 

that at an elevation of 4392 metres the red cells had increased from 
5,000,000 to 8,000,000, many of them being undersized. In the blood 
of animals he found a similar polycythemia but no increase in oxygen. 

These observations were verified by Egger, Koppe, Wolff, and 
many others, who found that the increase begins almost immediately 
upon the change in altitude, amounting at times to 1,000,000 cells 
in twenty-four hours, while Campbell and Hoagland calculated that 
there is an increase of 50,000 cells for every 1000 feet of elevation. 
The increase reaches its limit in about two weeks, after which the 
numbers tend slowly to diminish. On returning to sea level the 
polycythemia promptly disappears, even more rapidly than it is 
established (Mercier). The percentage of Hb appears to be less 
affected, and the volume of red cells not at all. Egger found no 
change in the dry residue of the blood of two rabbits, but Grawitz 
found the residue distinctly increased in a rabbit which had been con- 
fined in a rarefied atmosphere. The blood of anemic and phthisical 
patients is less markedly and permanently affected than that of healthy 
individuals. 

The significance of these changes has not been fully explained, but 
it seems most probable that the polycythemia is an effect of concen- 
tration of the blood, brought about by lowered blood pressure, and 
tending to readjust the respiratory function to the smaller proportion 
of oxygen in the rarefied atmosphere. That the state of the blood 
is one of simple concentration is, however, rendered uncertain by the 
low percentage volume of red cells. Egger and Koppe maintain 
that there is a formation of new red cells, finding a sudden increase 
of small cells soon after the ascent, while at the end of the period 
there are four to eleven small cells to one large one. These micro- 
cytes, however, cannot figure as evidence of new formation of cells. 
]S"ormoblasts ought to be present if, as Grawitz says,^ about one litre 
of new blood has been produced in twenty-four hours, while the 
polycythemia promptly subsides at sea level without yielding signs 
of blood destruction. The possibility that the cells are concentrated 
in the capillaries is denied by Egger, who found a similar increase in 
the large internal arteries of rabbits, and claimed by Campbell and 
Hoagland, among others, who found the red cells diminished in the 
blood of the mesentery while increased in the ear. The suggestion 
of Fick that the red cells may enjoy a lengthened existence in the 
circulation does not commend itself. 

Several observations, recently reviewed by Starcke, indicate that 
the results obtained by the hematocytometer vary to some extent 
with the temperature and barometric pressure, and Zeiss constructs 
a special counting-chamber, allowing a free circulation of air beneath 
the cover-glass for use in high altitudes. It has not, however, been 
found possible to refer the polycythemia of high altitudes to factors 
of this sort. 

Residence at the seacoast is frequently followed by increase in 
the number of red cells as a part of improvement in general health. 

In the tropics most Europeans becomes more or less anemic until 
fully inured to the various uuhygienic influences obtaining there. 



MOJRPHOLOGY AXB PHYSIOLOGY OF BED CELLS. 109 

The Polycythemia of Diarrheal Diseases. The concentration 
of the blood which results from depletion of flnids through the in- 
testine is seen to a slight extent in severe simple diarrhea, more dis- 
tinctly in acute dysentery and at its height in cholera. 

An increase of two millions in the number of red cells has 
been observed by Hay within two hours after the administration of 
21 grm. of Glauber's salts in concentrated solution, and Brouardel 
demonstrated less clearly a marked increase after purgation by croton 
oil and jalap. AYhen given in a dilute solution the effects of the 
salines are, of course, less evident. Clinically, a moderate polycy- 
themia has been observed after severe diarrhea or vomiting, but the 
effects are usually transient. 

In dysentery, polycythemia may be expected only when the diar- 
rhea is acute and the quantity of blood lost is slight. Usually an 
anemia is established by direct loss of blood. 

In typhoid fever the progress of the anemia is often greatly 
obscured by the concentration of blood in cases marked by severe 
diarrhea. In cholera the conditions are especially favorable for 
watery depletion of the blood and tissues, and remarkably high 
counts have been recorded in the late stages of this disease. 

Polycythemia of Endocarditis, Venous Stasis, etc. Very 
numerous observations have shown that at some stages of endocar- 
ditis a marked polycythemia is established, and largely through the 
studies of Oertel and of Grawitz it has been shown that this concen- 
tration is found in conditions marked by chronic stasis, cyanosis, 
edema, and is more marked in the capillaries than in the veins or 
arteries. The same condition is seen in chronic stasis from other 
causes (Peiper, Grawitz^). 

Phosphorus Poisoning. In cases of phosphorus poisoning of 
moderate intensity, but fatal, Taussig observed an increase in red 
cells to 8,500,000,' v. Jaksch an increase from 4,300,000 to 8,250,000 
and Limbeck an increase to nearly 8,000,000. The fact that the 
polycythemia does not appear until the toxic symptoms are marked, 
and usually subsides with them about the fourth or fifth day, indi- 
cates that it results largely from depletion of the blood through the 
vomitus. V. Jaksch found no simultaneous increase in the propor- 
tion of albumins. The leucocytes are usually diminished, sometimes 
slightly increased, and the Hb-index is lowered. 

Illuminating Gas Poisoning. Munzer and Palma. and Limbeck 
have observed moderate polycythemia in three cases (5,700,000, 
6,630,000, 5,700,000), with slight leucocytosis, 13,300 in one case. 
The condition must be referred to venous stasis. 

Polycythemia after Cold Baths. An increase of red cells of 
500,000 to 1,500,000 has been observed by many writers to occur 
after the application of cold baths (Toenissen, Winternitz, Knopfel- 
niacher, Thayer). The change is observed immediately after the bath, 
and continues after cyanosis has disappeared and while the patient is 
shivering, but soon disappears thereafter. It is often missing after 
fifteen to twenty minutes. The leucocytes are also usually increased 
(15,000 to 20,000). The condition is probably referable to concentra- 



1 1 GEXERAL PHYSIOL OGY AXD PA THOL G Y. 

tion of the blood due to stimulation of the vasoconstrictors, and is 
probably more marked, if not exclusively present, in the peripheral 
capillaries. Yet some have suggested that a new formation of cells 
may be indicated by the change. It may be noted here that warm 
baths have a contrary effect. 

Effects of Surgical Procedures upon the Blood. Anesthesia. 

Several painstaking studies have been contributed in the last few 
vears in the endeavor to determine what effects upon the blood are 
produced by the administration of ether and by the procedures 
required in a surgical operation. 

(a) Effects of Ether. Chadbourne coimted the leucocytes before 
and after etherization, but before operation, in twenty cases, most of 
whom exhibited leucocytosis from some inflammatory condition. 
He found an increase of leucocytes in each instance, often slight, but 
sometimes well marked, averaging 37 per cent. The increase was 
most marked in the early stages of anesthesia. Differential counts 
in five cases showed very slight variations in the proportions of the 
different types of cells. 

Of 50 cases examined under similar conditions, Cabot, Blake, and 
Hubbard found the leucocytes decreased in 7, increased less than 
2000 in 30, more than 2000 in 13, and more than 10,000 in 1 case. 
The discrepancy in the above results may be explained by differ- 
ences in the methods of estimatiug the leucocytes and of administering 
the ether and in the character of the cases under observation, and it 
may only be said that etherization of human subjects requiring 
operation usually increases the leucocytes to a slight degree (2000), 
but sometimes very markedly, or, again, may not increase them at 
all or even cause considerable diminution. More uniform results 
may perhaps be obtainable from experiments upon animals. Oliver 
etherized eight rabbits for one hour, finding the red cells diminished 
on the average 0.03 per cent., far within the limit of error in calcu- 
lation. In three rabbits the writer found no appreciable difference 
in the leucocytes of the jugular vein before and after full etherization. 

(6) Effects of Ether and Operation. Most of the studies in this 
field concern the changes in the blood after operation. 

Da Costa and Kalteyer, in fifty cases, found the red cells increased 
149,000 (average), Hb reduced 3 per cent., and leucocytes increased 
4586. They found reason to believe that the preparatory treatment 
of the patient by fasting and purging concentrates the blood to some 
extent. 

Frazier and Holloway, in forty cases, found very slight changes in 
the red cells and Hb, as the following table shows : 

Forty-eight 
hours after. 
79.S 



Before 


Three 


Tvrenty-four 


operation. 


hours after. 


hours after. 


Hb., 81.8 per cent. . 


. 82.9 


S1.6 


Red cells, 5.49 mil. 


, 5.58 


5.53 



O.'J, 



The leucocytes invariably increased, sometimes very markedly, in 
seven cases of malignant tumors from 11,000 to 24,777 ; in twelve 



MOBPHOL G Y AND PH YSIOL OGY OF RED CELLS. 1 1 1 

inflammatory cases, from 12,498 to 20,414, and in twenty-one non- 
inflammatory cases from 9748 to 20,053, 

Very similar results in the study of leucocytosis after operation 
have been reported by v. Lerber, White, Cabot, Blake, and Hub- 
bard, but in five of forty-seyen cases of the last-named observers 
there was a decrease of ^yhite cells. 

Frazier endeavors to analyze results with regard to many factors 
concerned with the operation. He concludes that the leucocytosis 
increases in general with the extent of the operation, is not affected 
by fever, nor by the administration of ordinary drugs, by vomiting, 
sweating, purging, or pain. The usual dressings have very slight 
influence. Hemorrhage may cause considerable increase. Imper- 
fect drainage of the wound, with collections of fluids and infection of 
the wound, always cause increase of leucocytes. In uncomplicated 
cases the leucocytes returned to the normal in about three and one- 
half days in Frazier^s cases ; in thirty-six hours in Cabot's ; in 
twenty-four hours in Bloodgood's, and not until five days in White's 
celiotomies. In many cases the fall should be progressive after 
twenty-four hours, otherwise a complication may be suspected. 

The results of the above cases are of importance in emphasizing 
the great variety of factors which must be considered in the inter- 
pretation of blood analysis and in the conclusion, which seems to be 
unanimous with the above wTiters, that complete routine examina- 
tion of the blood is a necessary feature of the correct management 
of surgical cases. 

Influence of Therapeutic Measures on the Red Cells. 

Iron. The remarkable effect of this agent upon the blood in suit- 
able cases of anemia is seen in a rapid increase in the number of red 
cells and in a later but rather more uniform increase of Hb. Accord- 
ing to Hay em the effects of iron in chlorosis may be divided into 
two periods, in the first of which the increase in red cells outstrips 
that in Hb until a normal number is reached, while in the second 
period the Hb of the new red cells is gradually brought to the 
normal. The appearance in such cases of many small red cells 
deficient in Hb has been commonly noted, but Stifler finds they are 
not equally abundant at all periods of the regeneration of the blood, 
that the increase of cells occurs j)eriodically, and that at the height 
of the periods many pale cells are found which increase in Hb-content 
while the numbers of cells remain nearly constant. 

Again, Willcox finds a difference in the effects of small and of 
large -doses of iron. When small doses are used the red cells out- 
strip the Hb, but with large doses both increase in equal proportion. 
Laache also has observed equal progress in cells and Hb in cases of 
chlorosis. It would seem, therefore, that the regeneration of the blood 
under iron may follow any one of the above three courses, depending 
upon various circumstances which cannot here be further discussed. 

Hay em and Reinert have called attention to the tendency of the 
red cells to diminish slightly after reaching a normal number until 



112 GENERAL PHYSIOLOGY AND PATHOLOGY. 

the restoration of Hb becomes complete. Of the two Reinert 
believes that the progress of the Hb is the more uniform. Limbeck 
finds that the red cells nsually diminish for some days when the 
administration of iron is begun. 

Indications for the Use of Iron. The specific effects of this drug 
being centred primarily on the Hb, the chief indication for its use 
and the best results are obtained in cases of pure chlorosis with 
marked loss of Hb and moderate reduction in cells. In secondary 
anemia its curative action is less certain. With the appearance of 
larger cells iciih normal or increased Hb the use of iron becomes much 
less effective, and when the Hb-index is above normal it seems to be 
entirely valueless. 

A large part of the effects attributed to iron may be obtained 
solely by the improved hygienic and dietetic conditions which are 
usually enjoyed during its administration. The influence of rest in 
bed, selected diet, baths, oxygen, massage, etc., has long been recog- 
nized as a very powerful adjunct in the treatment of anemia. But 
numerous observations go to show that while the numbers of 
cells may be greatly increased by these means, yet the complete 
restoration of Hb in severe chlorosis is seldom as complete or rapid 
as w^hen iron is freely given, so that a specific influence of this drug 
must be admitted. This fact is clearly indicated in Aporti's experi- 
ments on animals subjected to repeated bleedings, in which recovery 
was greatly retarded on iron-free diet and markedly and promptly 
facilitated by injections of iron. 

Of the great variety of preparations employed at various times, 
probably the more irritant preparations in large doses are still 
acknowledged to yield the best results when well borne by the 
stomach. 

The curative action of iron in anemia is still largely unexplained, but the 
theory of Binz appears to remain most rational. Binz holds that in chlorosis, 
as a result of prolonged malnutrition, the absorption of iron from the food 
becomes deficient, while its excretion through the liver and bile remains undi- 
minished, and the blood becomes impoverished in this principle. By admin- 
istering iron in large doses it is more readily absorbed and the deficiency is 
overcome. 

Bunge's theory, based on Sir Andrew Clark's belief that chlorosis is an auto- 
intoxication of intestinal origin, assumes that the iron administered is not 
absorbed in increased quantity but exerts its curative influence by neutralizing 
toxic agents in the intestines. These assumptions have been largely disproved 
by V. Noorden, Rethers, and Morner, who have demonstrated that abnormal 
putrefactive processes in the intestine are not usually present in chlorosis, and 
by the demonstration that increased ingestion of inorganic iron is followed by 
its increased absorption principally or exclusively in the duodenum (Kunkel, 
Woltering, Hall, McCallum, Hochaus and Quincke, Cloetta, Hoflfman), After 
intravenous injections of iron Jacobi found that 10 per cent, promptly appeared 
in the excreta, 50 per cent, lodged in the liver, the rest in other organs, while 
the blood was free from excess after three hours, v. Noorden's- conclusions 
seem to embody the results thus far obtained, that while iron in the nucleo- 
proteid combinations of the food is constantly available in chlorosis, it is either 
not absorbed or is not appropriated by the blood, whereas when given in large 
doses it is absorbed in excess and exerts a specific influence upon the bone- 
marrow. The problem of the nature of this influence remains, of course, 
untouched. 



MORPHOLOGY ASD PHYSIOLOGY OF BED CELLS. 113 

Arsenic. AVhile iron is contraindicated by the appearance in the 
blood of megalocytes with increased Hb, under these circumstances 
arsenic frequently exerts an almost specific effect in increasing the 
number of red cells and in stimulating the production and more 
uniform distribution of Hb. Its field is, therefore, chiefly in the 
severe and chronic anemias, but in the simpler forms the action of 
iron is often accelerated by combination with arsenic. In chlorosis 
arsenic is said to increase the red cells much faster than the Hb 
(Riva), and to stimulate the development of more resistant cells 
(Bettman). Its therapeutical effects in disease are rendered more 
obscure by the fact that in health it causes diminution in the number 
of red cells (Stierliu, Delpeuch). Stockman and Greig claim to 
have found evidences of increased formation of red cells in the 
marrow of rabbits after long use of arsenic, yet the number of red 
cells in the blood remained normal. 

Mercury. Numerous observations upon the effects of mercury in 
syphilis, dating from those of Wilbouchewitch and Keyes, in 1874-76, 
to those of Lezius and Martin and Hiller, in 1890, have failed to 
demonstrate that this drug in therapeutical doses has any direct effect 
upon the red cells. It has been shown, however, that in doses 
beyond a limit which varies with individuals and circumstances, 
mercury usually causes a prompt reduction in both cells and Hb, 
and distinct anemia. It does not appear, from these studies, that 
the improved condition observed in the blood of syphilitics using 
mercury is separable from the removal of the virus and the conse- 
quent general improvement in health. A reduction in Hb and cells 
has been frequently observed soon after beginning mercurial treat- 
ment or after the drug has been pushed and seems to continue until 
the system becomes inured or the dose has been reduced to a proper 
limit, so that the examination of the blood, as shown by Martin and 
Hiller, may be made a valuable guide in the administration of this- 
remedy. Most of the conflicting results reported may be explained 
on the grounds that in doses beyond a variable limit, especially at 
the beginning of treatment, mercury reduces the cells and Hb ; that 
when the original disease is being successfully combated the anemia 
usually improves ; and that apart from its antisyphilitic powers the 
drug has little effect upon the blood. (See section on Syphilis.) 

Lead. In cases of chronic lead poisoning the blood commonly 
shows a moderate grade of secondary chlorotic anemia. Zinn 
records an acute case with hemorrhages in which the red cells 
numbered 4,000,000, leucocytes 3300, Hb 58 per cent., s. g. 1048. 
More severe cases have been reported with anemia, usually in pro- 
portion to length of the disorder, by Malassez, 2,200,000 red cells ; 
by Limbeck, 2,200,000; and by Brochin, 1,300,000. Hayem 
states that the anemia of chronic plumbism is characterized by its 
close resemblance to chlorosis, by the rapid decrease in cells while 
the patient suffers from colic, and by the absence of leucocytosis. 
Hayem saw no case with increased Hb-index, but Malassez re- 
ported megalocytes and megaloblasts as abundantly present in some 
cases. 



114 GENERAL PHYSIOLOGY AND PATHOLOGY. 

This anemia is commonly attributed to gastro-intestinal disturb- 
ance, but Hayem referred it to destruction of cells from direct action 
of lead, 

Maragliano demonstrated increased globulicidal activity of the 
serum in chronic plumbism, and Grawitz has noted considerable 
degrees of granular degeneration of the red cells. 



OLIGOCYTHEMIA. 

Hemorrhage causes a peculiar type of impoverishment of the 
blood in which the oligocythemia is associated with other important 
changes in the plasma. The progress of events in the circulation 
which follow a severe loss of blood involves the consideration of 
many physiological processes. One of the first effects is a lowering 
of blood pressure, which is followed by an increased flow of lymph 
and by a rapid transfusion of fluids from the tissues through the 
capillary walls. The fluid which replaces the lost blood is neces- 
sarily of different composition from the plasma, and its addition to 
the circulation markedly affects the composition of the blood a"fter 
hemorrhage. The lymph, being rich in salts and poor in albumins, 
and water from the tissues passing through capillary walls more 
readily than albumins, the blood when restored to its normal volume 
is found to be low in albumins, rich in salts, and poor in red cells. 
After rapid hemorrhages the alkalinity of the blood falls (Zuntz), 
and its content in sugar increases (Bernard, Mering), this principle 
being derived from the glycogen of the liver (Schenck), while the 
coagulability is much increased. The hydremia affects principally 
the plasma, but Herz found the relative volume of the red cells 
tripled ten hours after a very severe hemorrhage, indicating that they 
had absorbed much water. 

In small animals (rabbits) the restoration of the volume of blood 
takes place very rapidly and oligocythemia is observed almost imme- 
diately after the hemorrhage, but in larger animals (dog, man) a dis- 
tinct interval is required before the fluids have replaced the lost 
blood, and, according to Limbeck, thirty-five to forty minutes may 
elapse before a distinct reduction in red cells is observed after 
moderately severe hemorrhages. 

The changes in the number of red cells following hemorrhages are 
somewhat irregular, but from the observations of Huhnerfauth, Lyon, 
Otto, Koeppe,^ Viola and Jona, it has been shown that in dogs and 
man a single large hemorrhage reduces the red cells in proportion 
considerably less than the effect upon the volume of blood, beginning 
about one-half hour after the operation, reaching a maximum effect 
in three to four days, and followed by a restoration to the normal 
number in nineteen to thirty-four days (Lyon). 

In small animals (rabbits) the rate of decrease is more rapid, the 
lowest point being reached in a few hours, and recovery also follow- 
ing earlier. With slow hemorrhages of large extent (3 to 4 per cent.) 
the minimum is reached in one to nine days, depending largely upon 



MORPHOL OGY AXD PH YSIOL OGY OF BED CELLS. 115 

the size of the animal, and recovery is complete in fourteen to 
twenty-two days (Huhnerfanth). After lesser hemorrhages (1 to 3 
per cent.) full recovery follows in five to fourteen days, while small 
losses leave no trace after two to five days (Lyon). These periods 
depend much upon the state of nutrition, and it has been found that 
full diet, free supply of water, and transfusion of salines greatly 
accelerate recovery. Ehrlich believes that the continuous reduction 
in cells is partly referable to the solution of many of them as the 
plasma becomes more watery. 

Dawson's experiments support this belief for cases in which in- 
fusion is practised, as he found the red cells to show diminished 
resistance, while the freezing point of the serum was unaltered. 
Limbeck and Pick also found that the albumins of the serum are 
restored within forty-eight hours. 

During both phases the Hb falls behind the changes in the cells 
(Otto, Reinert), owing to the formation of numerous microcytes by 
the splitting of red cells (Koeppe). Grawitz, however, does not 
believe that such splitting of red cells can occur. Nucleated red cells 
of normal or very small size appear within a few hours and in larger 
numbers after severe hemorrhage, and even after small losses, if 
sudden. That they are draw^n into the circulation mechanically is 
indicated by their usual absence after slow bleedings of much larger 
extent (Zenoni^). 

Changes in the size and shape of the cells are commonly observed, 
especially after large bleedings. Microcytes and slightly enlarged 
megalocytes usually appear in two to four days, at the period of 
greatest oligocythemia (Koeppe.) The extent and duration of these 
changes depend largely on the grade of anemia established. Poly- 
chromatophilia is usually marked within twenty -four hours. 

Healthy men recover rapidly from moderately severe hemorrhages 
and so completely that the red cells may be more numerous than 
before, from apparent overstimulation of the marrow (Otto, Hall 
and Eubank). Small and repeated hemorrhages, on the other hand, 
have led to some of the most severe forms of anemia ever recorded, 
in which the morphological changes of pernicious anemia are pro- 
nounced, but the prevailing feature of the blood is the loss of Hb. 

From very extensive observations in Mickulicz's clinic, Bierfreund 
found that the regeneration of the blood is most rapid in male sub- 
jects between twenty and forty years of age, is considerably earlier in 
males than in females, and in adults than in children or old persons. 
A loss of 5 per cent. Hb was found to lengthen the period of regen- 
eration two to eight days. The minimum percentage of Hb was 
reached, after a loss of 10 to 15 per cent., in 3.5 days ; after 16 to 20 
per cent., in 5.8 days ; after 21 to 25 per cent., in 6.5 days ; after 26 
per cent., in 9.6 days, and in women usually one day later than with 
men. 

It is significant that in Bierfreund's tables there are no averages 
on patients losing more than 30 per cent, of Hb, indicating that when 
a surgical operation causes a loss of 30 per cent, of Hb it is usually 
fatal. Mickulicz attempted to deduce from this fact the rule that 



116 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



no operation should be undertaken unless the patient could stand 
such a loss, but it is difficult to see any great practical application of 
such a rule. 



Bierfreund's Table, Showing Average Time of Full Regeneration 
OF Blood after Hemorrhage. 


Loss of blood 


Male. 


Female 


Age (years). 


Ht) per cent. 


1-10 


10-20 


20-30 30-40 


40-50 


50-60 


60+ 


10-15 . . . 


12 7 


17.1 days 


20 


13.2 


10.8 


10.4 


16 


17 




16-20 • . . 


17 9 


23.5 


21 


19.0 


12.5 


16.2 


.21 


22.7 


23.8 


21-25 . . . 


20.3 


23.5 


22.5 


21.3 


17.6 




19 


28.0 


27 


26 . . . 


27 


31.3 

















Anemia following Repeated Small Hemorrhages. While very 
marked changes in the blood following a single large hemorrhage 
may be rather promptly restored, the regeneration is very greatly 
retarded after even one repetition of the hemorrhage, and when they 
are frequently repeated there is soon established a severe form of 
chronic anemia. It does not appear that this anemia differs greatly 
from other equally severe secondary forms, but it is usually char- 
acterized by marked reduction in the albumin (less of the globulin) 
of the plasma and serum ; by lowering of the dry residue and ash, 
due to loss of Fe, P, and K, which more than balances the increased 
Na, and by lowered alkalinity. Besides the actual withdrawal of 
albumin, repeated hemorrhages seem to have almost a specific effect 
in increasing fat formation at the expense of albumin both of the 
blood and tissues (Leube). 

The loss of red cells is here an accurate measure of the grade of 
anemia, and all ordinary forms of their degeneration are observed. 
In mild cases the loss of Hb is relatively slight, but in some severe 
cases the Hb percentage and index are very low. On the other 
hand, there can be no doubt that the state of the blood following 
repeated small hemorrhages cannot always be distinguished from that 
of primary pernicious anemia with increased Hb-index. Anemia 
from hemorrhages is one of the secondary forms most commonly 
marked by leucocytosis, yet this feature is often not marked and is 
not infrequently absent. 

With man and animals the clinical effects of hemorrhage vary 
greatly among individuals. Bechamp and Huhnerfauth find that 
dogs withstand the loss of 3 to 4 per cent, of the body weight, 30 to 
40 per cent, of the total volume of blood, if the loss is gradual, but 
may perish after smaller but more rapid bleedings. As a rule, the 
smaller the animal and the more rapid the hemorrhage the more 
severe are its effects. Adult male subjects usually die if losing 
rapidly 50 per cent, of the blood, but may survive much greater 
losses from slow bleeding. Children are much more susceptible, and 
may die after very small hemorrhages, if rapid, while women Avith- 
stand effects of hemorrhage much better than children or men. The 



3I0IiPH0L0CrY ANB PHYSIOLOGY OF BED CELLS. 117 



regeneration of the blood, however, is more rapid in men than in 
women (Bierfreiind). 

The quantity of blood wdiich may be lost without causing death 
varies greatly among individual men and animals, as the following 
table will illustrate : 

Limits of Hemorrhage from Which Recovery Has Been Observed. 



Author. 


Animal. 


Percentage of body weight 
lost. 


Percentage 
of red cells 
remaining. 


No. of 

red cells 

remaining. 


Vierordt .... 


Dog. 
t< 

(< 

Rabbit. 

Man. 
Woman. 

2 hemor- 
rhages in 
6 days. 




50 

50 
32 
11 




Hayem 

Kireeff 

Maydel 

Schram 

Landerer .... 

Feis 

Andral, Behier . 


4. 33-5. 55 
4. 3 -7. 3 
5. 48-6. 57 
average 
5.12 
4. £8 5 4 5. 44 
(not (even (always 
fatal). chance). fatal). 
4.5 
3.0 




Laache 




(1,598,000 
1 1,415,000 


Hayem 









TRANSFUSION OF SALT SOLUTION, SERUM, AND 
DEFIBRINATED BLOOD. 

Siegel and Schram both found no improvement in the regeneration 
of the blood from the transfusion of salt solution or of serum in 
animals after bleeding, and while it has since been shown that the 
regeneration is somewhat more rapid and complete after salt infusion, 
yet this procedure must be regarded as of more value as a means of 
saving life than as a stimulant to blood formation. The direct 
effects on the blood of infusion of defibrinated blood seem to be 
much more favorable. On the other hand, after the transfusion of 
blood the above observers and others have found a rapid increase 
in the number of cells, and Bizzozero reported the same effect after 
transfusion of defibrinated blood in animals. Quincke was one of 
the first to note an increase in red cells in pernicious anemia as a 
result of transfusion of blood, and similar observations have been 
made by Ziemssen in anemia and scurvy. It would seem from the 
observations of Bizzozero and of Bareggi that the red cells are quite 
resistant to the process of defibrination and injection. Of the imme- 
diate effects of salt infusion upon the blood of the human subject there 
are a few reports at hand which indicate that it has considerable influ- 
ence in lowering the numbers of red cells and increasing the leucocytes. 



ORIGIN OF SECONDARY ANEMIA. 

The anemia associated with acute and chronic diseases is a result 
of many factors of varying prominence in different conditions, and 
requiring consideration in detail. 



118 GENERA L PH YSIOL OGY AND PA THOL OGY. 

Diminished Nutrition. Since the digestive powers are largely in 
abeyance in severe febrile states the loss of the usual supply of 
albuminous principles must figure to some degree in the impoverish- 
ment of the blood. Although the complete withdrawal of food in 
healthy men leads to a simple " atrophy of the blood/^ with other 
tissues, marked by diminution in bulk, polycythemia, etc., but not 
to anemia (Heidenhain, Voit), it by no means follows that similar 
results would occur in disease, while distinctly anemic conditions 
are known to result from improper quality of food (Leichtenstern). 
Grawitz has found that food deficient in albumin may cause a 
diminution in the albumin of the plasma, which may be demon- 
strated within four to eight days, is more marked when the subject 
is exercising, and later affects also the number of cells. 

Diminished Activity of Blood-forming Organs. Simultaneously 
with the loss of digestive powers it can hardly be doubted that the 
normal process of red-cell formation must be interrupted in most 
infectious diseases. This conclusion may be based upon the known 
effects of toxemia upon cellular processes, or the absence of normal 
stimulus from absorbed food products, and upon anatomical condi- 
tions demonstrated in the bone-marrow. Regarding the last factor 
it may be said that the leucocytosis of pneumonia is associated with 
proliferation of myelocytes in the marrow at considerable expense 
of normoblasts, and in typhoid fever the normal relations in the 
marrow cords are greatly disturbed by congested, dilated, or even 
ruptured sinuses. 

Increased Consumption of Albumins. The toxic destruction 
of albumins in fever has been fully demonstrated by Hallervorden 
and Leube,^ and their products noted in the increased excretion of 
urea, of urinary pigment (Jaffe), and potash salts (Salkowski). 
While the tissue proteids suffer most in this process it is but a step to 
the source of these principles in the blood. That the albumins of the 
blood and tissues suffer in some degree in afebrile cachexias is indi- 
cated by the results of Miiller's studies on metabolism in carcinoma. 

Increased Destruction of Red Cells. The increased globulicidal 
activity of the serum in infections and septic processes is undoubt- 
edly a most potent agency in the diminution of red cells, and has 
been demonstrated by Maragliano in carcinoma, pneumonia, typhoid 
fever, erysipelas, tuberculosis, and many other conditions. The 
very rapid deglobulization observed in malignant endocarditis and 
septicemia leaves abundant evidence of this peculiar process also in 
the pigment deposits found in the viscera. Of the sources of the 
globulicidal agent little is known, but it is certain that the products 
of disordered tissue metabolism and bacterial toxins are capable of 
dissolving red cells when injected into the circulation. Fischer and 
Adler saw the red cells fall from 6,000,000 to 1,300,000 in seven days 
after injections of streptococcus cultures into a rabbit ; and Grawitz 
could find only 300,000 red cells in a remarkably rapid case of 
streptococcus septicemia in an adult woman. Bianchi-Mariotti found 
a marked loss of Hb in direct proportion to the quantity of culture 
used after injections of cultures of B. typhosus, cholera, anthrax, etc. 



MOEPHOL G Y AND PH YSIOL OGY OF BED CELLS. 119 

There is abundant evidence to sbo^Y that in many conditions asso- 
ciated with acute infection and resulting from chronic cachexia 
the red cells are abnormally fragile. Of such evidence may be 
mentioned the occurrence of paroxysmal hemoglobinemia on slight 
exposure to cold, and the rapid development of anemia in many 
mercurialized subjects. 

Loss of Blood by Hemorrhage and Exudation. Perhaps the 
majority of severe cases of secondary anemia result from the com- 
plication of the original disease by single or repeated hemorrhages. 
Post-typhoid anemia is usually slight and sometimes absent if there 
have been no bleedings from the intestines, and cancerous cachexia 
is very promptly aggravated when ulceration and hemorrhage super- 
vene. Much of the anemia in anchylostomiasis is referable to minute 
hemorrhages. 

Of the depleting effect of albuminous and bloody exudates good 
examples are seen in the acute anemia of exudative nephritis (Die- 
balla), and in the hemorrhages of the infectious purpuras, tubercu- 
lous pleurisy and malignant endocarditis. 

Chronic suppuration leads to a peculiar form of cachexia with 
waxy changes in the viscera, and severe anemia. 

By the interaction of these various factors there usually results 
in infectious diseases and cachexias a certain grade of secondary 
anemia. Yet, notwithstanding the many contributing causes, acute 
infectious diseases, e. g., typhoid fever, may run their course with 
no demonstrable reduction in red cells, and it is a rule of frequent 
application that associated conditions in these diseases obscure the 
actual state of the blood and tend to diminish or exaggerate the true 
degree of anemia. 

The polycythemia of cholera is an example of one extreme condi- 
tion of this sort, partially illustrated also by the slight polycythemia 
sometimes observed in typhoid fever. 

In dropsy the state of the blood accords with the watery condition 
of the tissues, and anemia is apt to be exaggerated. Grawitz has 
found that injections of extract of cancerous tumors greatly accelerate 
the flow of lymph into the circulation and are followed by reduction 
of red cells. 

The morphological changes in the blood of secondary anemias have 
been rather fully described in an extensive literature upon this sub- 
ject, and will be detailed later. Of the chemical changes very much 
less is known, although it can readily be seen that the varying 
prominence of the above factors probably leads to very different 
chemical alterations. To what extent constant chemical peculiarities 
can be established for the secondary anemias of Avidely different 
origin, e. g., hemorrhages and syphilis, remains to be decided, but at 
present there is no evidence to show that any uniform chemical 
changes distinguish one form of secondary anemia from another 
(Ehrlich). 



120 GENERAL PHYSIOLOGY AND PATHOLOGY. 

Bibliography. 

Morphology and Physiology. 

Andral, Behier. Cited by Reinert. 

Andriezen. Diss., Dorpat, 1883. 

Aporti. Cent. f. kl. med., 1900, p. 41. 

Askanazy. ^ Zeit. f. klin. Med., Bd. 23, p. 80. ^ Zeit. f . klin. Med., Bd. 21, p. 415. 

Bechamp. Compt. Rend. Acad. Sci., T. 88, p. 1327. 

Behrendt. Dent. med. Woch., 1899, No. 44. 

Bernard. Cited bv Schenck. 

Bert. Compt. Rend. Acad. Sci., 1882, p. 805. 

Bettman. Ziegler's Beit., Bd. 23. 

Bidder, Schmidt. Cited by Limbeck. 

Bidone, Gardini. Archiv "ital. de Biol., 1899, p. 36. 

Bierfreund. Langenbeck's Archiv, Bd. 41, p. 1. 

Binz. Vorles. u. Pharmacol., 1884. 

Bloodgood. Medical News, vol. 79, p. 321. 

Brochin. Gaz. des Hop., 1875, No. 24. 

Brouardel. L'Union Med., 1876, No. 110. 

Brucke. Sitzb. k. Ac. Wissen., Wien, 1867, Bd. 56, Abt. 2, p. 79. 

Bunge. XIII. Cong. inn. Med., 1895. 

Cabot, Blake, Hubbard. Ann. of Surgery, vol. 34, p. 361. 

Campbell, Hoagland. Amer. Jour, of Med. Sci., vol. 122, p. 654. 

Chadbourne. Phila. Med. Jour., vol. 3, p. 390. 

Cloetta. Archiv f. exper. Path , Bd. 38, p. 161. 

Da Costa, Kalteyer. Annal. of Surg., vol. 34, p 329. 

Dawson. Amer. Jour, of Physiol., vol. 4, p. 2. 

Dieballa. Deut. Archiv klin. Med., Bd. 57, p. 302. 

Dunin. Volkmann's Vortrage, N. F., 135. 

Duperie. These de Paris, 1878. Jahresb. d. ges. Med., 1879, Bd. I., p. 39. 

Egger. XII. Cong. inn. Med., 1893. 

Ehrlich. ^Charite Annalen, Bd. 10, p. 136. ^ Die Anemie, T. 2, p. 116. 

Engel ^ Deut. med Woch., 1899, p. 209. ^ Verh. d. Yerein. inn. Med., Berlin, 
1899. 

Ewing. N. Y. Med. Jour., vol. 61, p. 257. 

Feis. Virchow's Archiv, Bd. 138, p. 75. 

Pick. Pfliiger's Archiv, Bd. 60, p. 589. 

Foa. Jour, of the Micros. Soc, vol. 2, p. 198. 

Frazier, Holloway. Univ. of Penn. Med. Bull., vol. 14, p. 363. 

Frederickson. Diss., Dorpat, 1888. 

Gabritschewsky. Archiv f. exper. Path., Bd. 28, p. 83. Zeit. f. klin. Med., Bd. 
27, p. 492. 

Graber. Zur. diag. d. Blutk., Leipzig, 1888. 

Grawitz. ' Berl. klin. Woch., 1900, p. 181. ^ Berl. klin. W^och., 1895, p. 1047. 
■^ Ibid., 1895, p. 713 * Zeit. f . klin. Med., Bd. 21, 22. ^ Deut. Archiv klin. Med., 
Ed. 54, p. 588. 

Hall. Archiv f. Anat. u. Phys., Phys. Abt., 1896, p. 49 

Hall, Eubank. Jour, of Exper. Med., vol. 1. 

Hallervorden. Archiv f. exper. Path., Bd. 12, p. 237. 

Hamburger. Zeit. f. Biol., 1890, p. 259. 

Hay. Jour, of Anat. and Phvsiol., vol. 16, p. 430. 

Hayem. Compt. Rend. Acad.' Sci., T. 84, p. 1166. 

Helling. Inaug. Diss., Dorpat, 1884. 

Helot. Cited bv Schiff. 

Herman, Groll. " Pfliiger's Archiv, Bd. 43, p. 239. 

Herz. Virchow's Archiv Bd. 133. 

Hochaus, Quincke. Archiv f. exper. Path., Bd. 37, p 159. 

Hoffman. Miinch. med. Woch., 1899, No. 24. 

Hosslin. Miinch. med Woch., 1890, p. 654. 

Huhnerfauth. Virchow's Archiv, Bd. 76, p. 310. 

Jacobi. Archiv f. exper. Path., Bd. 28, p. 256. 

Jaffe. Virchow's Archiv, Bd. 70, p. 411. 

V. .Jaksch. Deut. med. Woch., 1893, p. 10. 

Kireeff. Archiv f. Anat., 1884. 

Keyes. Amer. Jour. Med Sci., 1876, p. 17 



JIOBPHOLOGY AXB PHYSIOLOGY OF BED CELLS. 121 

Klein. Wien. med- Presse, 1896, p. 922. 

Knopf eJmacher Wien. klin. Woch., 1893, pp. 810, 886. 

Koppe. "■ XII. Cons;, inn. Med., 1893. =^ Miinch med. Woch., 1895, p. 904. 

Kunkel. Pfliiger's Archiv, Bd. 61, p. 595. 

Landerer. Archiv f. khn. Chir., Bd. 34. 

Lazanis. Dent. med. Woch., 1896, No. 23. 

Lenoble. Cited b}^ Lazarus. 

V. Lerber Diss., Bern, 1896, cited by Chadbourne. 

Leuhe. ^ Spec. Diag. imi. Krankh., ^ Leipzig, 1893, II., p. 296. ^ Vir chow's 
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LeziiLS. Inaug Diss., Dorpat, 1889. 

Luciani. Cited bv Grawitz. 

Luzet. These de Paris, 1891. 

Lyon. Vir chow's xVrchiv, Bd. 84, p. 207 

McCalhwi. Jour, of PhysioL, 1894, p. 268. 

Malassez. Archiv de Phvsiol., 1872, p 32. 

Maragliano, Castellino. Zeit. f. klin. Med., Bd. 21, p. 415. 

Martin, Hiller. Med. News, May 17, 1890. 

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Moleschott. Wien. med. Woch., 1854, p. 113. 

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Muller Zeit. f. khn. Med., Bd. 16 

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Taussig. Archiv f. exper. Path., Bd. 30, p, 161. 

Thaijer. Johns Hopkins Bull, 1893, p. 37. 

Timofjewsky. Cent. f. Path., 1895, p. 108. 



122 GENERAL PHYSIOL OGY AND PA THOL OGY. 

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Ziegler. Festschrift f. Hegar, 1889. 

Zinn. Berl. klin. Woch., 1899, p. 1093. 

Zuntz. Cent. f. d. med. Wissen., 1867. 



CHAPTER IV. 

THE LEUCOCYTES AND LEUCOCYTOSIS. 
LEUCOCYTES. 

Morphology. In fresh blood leucocytes are colorless, rather 
highly refractive bodies, usually larger than red cells, cohering to 
one another and to the glass, and exhibiting a highly refractive, 
compact, or, in the large mononuclear cells, vesicular nucleus. 
Granules are invisible in the normal mononuclear cells of the circula- 
tion, but in the others minute opaque (neutrophile) granules are dis- 
tinctly apparent in the polynuclear cells, and large greenish refractive 
granules serve to fully distinguish the eosinophile cells. The proto- 
plasm of the mononuclear cells is homogeneous, and refractive in the 
lymphocytes, transparent in the large mononuclear. Ameboid motion 
begins promptly, especially on a warm stage, in the finely and 
coarsely granular cells, becomes most active usually after twenty to 
forty minutes, and may persist for hours. In some later stages of 
ameboid activity the granules may show extremely active, vibratory, 
dancing, and swarming movements in cell bodies or processes. These 
have been regarded as Brownian movements or as indicating struc- 
tural changes of approaching death of the cell. In many cells, 
especially in anemic blood, there appear from the first large and 
small clear spheroidal areas which on staining appear to be divided 
among watery vacuoles, or granules of fat, glycogen, or other degen- 
erative products. 

Varieties of Leucocytes. In stained specimens five varieties of 
leucocytes may be distinguished, viz. : 

1. Lymphocytes. 

2. Large mononuclear leucocytes. 

3. Polynuclear neutrophile leucocytes. 

4. Esoinophile leucocytes. 

5. Mast-cells. 

1. Lymphocytes are classed as (a) small and (6) large, the small 
cells being bfx to 8// in diameter, and the large ones 8/^ to lOfi. Both 
sizes exhibit a narrow rim of strongly basophile homogeneous or 
coarsely reticulated cytoplasm, and compact or coarsely reticulated 
spheroidal nuclei, which are usually less basophilic than the cyto- 
plasm. With ordinary stains these cells fail to show cytoplasmic 
granules, although exhibiting nodal thickenings of the cytoreticulum 
which sometimes resemble granules. After the Nocht-Romanowsky 
stain all lymphocytes usually show a variable number of large and 
small violet stained granules, and in some of the larger cells the 
number of these granules approaches that of the myelocyte. (Plate 



1 24 GENERA L PH YSIOL OGY AND PA THOL OGY. 

III.) The nuclei of lymphocytes usually contain nodal thickenings 
resembling nucleoli. While the nuclei of lymphocytes are usually 
spheroidal, there occur in normal blood, and especially in lymphemia, 
medium-sized, strongly basophilic, hyaline leucocytes with incurved 
or subdivided nuclei, which must be classed with lymphocytes. 

Ehrlich has described these nodal thickenings as nucleoli, although not able 
to demonstrate in them the specific staining reaction demanded by histologists 
for the identification of these structures. Jolly was unable to demonstrate true 
nucleoli in lymphocytes by his method (fixation in Fleming's solution) which 
succeeded in demonstrating nucleoli in some other leucocytes. Eosin, how- 
ever, by vital staining with pyronin methyl green demonstrated red nucleoli 
in green nuclei of lymphocytes, and regards this reaction as specific of the 
lymphocyte class. 

Some authors distinguish two types of lymphocytes, one of which, the 
myeloblast, they believe is an undifierentiated cell and the parent of all blood 
cells, while the other is a specialized cell derived from the other and retain- 
ing permanently the characters of the lymphocytes. (See Chapter V.) 

Ameboid motion in lymphocytes was first described by Schultze, the 
inventor of the warm stage, and has long been accepted by pathologists as a 
fact. Ehrlich, however, reasoning from the difference in chemotactic sensi- 
bility of neutrophile cells and lymphocytes, concluded that the latter possessed 
no ameboid properties, and his teaching has dominated current opinion for 
some years. Recently Wolff", Hirschfeld,^ and Almquist have described anew 
ameboid movements and the locomotion of lymphocytes in normal blood and 
in leukemia. They are best demonstrated by examining blood on a warm 
stage on Deejen's agar-salt medium. Usually the large lymphocytes and 
hyaline cells have been described as showing the most active changes, but in 
malarial blood the writer has followed extensive ameboid changes in lympho- 
cytes possessing little cytoplasm. (Plate III.) 

2. Large mononuclear leucocytes may be only slightly larger than 
lymphocytes, but many of them are the largest cells seen in normal 
blood. Their protoplasm is slighUy basophile and very finely reticidar, 
with nodal thickenings often resembling basic granules, while other 
cytoplasmic granules are usually demonstrable by the Nocht- 
Romanowsky method. Their nuclei are vesicular, rather coarsely 
reticulated, with one or two central nodal thickenings resembling 
nucleoli, but no true nuclei have as yet been demonstrated in these 
cells. The nuclei may be circular, or horseshoe-shaped (transitional 
leucocytes), or elongated. In Ehrlich's triacid solution the bodies 
of mononuclear basophile cells stain very faintly red. (Plate I.) 

3. Polynuclear* leucocytes are two or three times as large as the 
red cell. Their protoplasm is reticulated and possesses as integral 
parts of the reticulum protoplasmic neutrophile granules in consider- 
able number. The reticulum is otherwise very slightly basophilic, 
and may be demonstrated, with basophilic nodal thickenings or 
granules, by methylene blue. (Plates V. and YIL) Their nuclei 
are elongated and constricted, or composed of two or more lobes 
usually connected by threads of chromatin. These lobes are coarsely 

* The attempt to displace Ehrlich's old term " polynuclear " by the unfortunately derived 
"polymorphonuclear" seems to the writer ill-advised. The former designation has become 
firmly established, never leads to confusion, and seeing that polymorphism characterizes nuclei 
of other mononuclear cells, and that the lobes of the neutrophile cell are often separate, there 
appears to be no gain in accuracy by such a change. 



PLATE IL 




^^^k 





Normal Blood. (Eosin and Methylene Blue.) 



Fig. 1. Normal rouleau. 

Fig. 2. Red cell, extruding slightly basophilic (nuclear) contents as blood plates. 

Fig. 3. Lymphocyte. 

Fig. 4. Large mononuclear leucocyte with finely reticular cytoplasm. 

Fig. 5. Polynuclear neutrophile leucocyte, granules vmstained. 

Fig. 6. Eosinophile leucocyte. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 125 

reticulated and usually possess a central nodal thickening, but true 
nucleoli have not been demonstrated. The lobes may become com- 
pletely separated from each other. 

Arnold,"^ Schur and Lowy, and Hirschfeld- have described the basophilic 
granules of the polynuclear leucocytes, the latter observer suggesting that 
they represent a basophile substratum of the neutrophile granules, and that 
their presence indicates that the cell is young. The writer regards it as uncer- 
tain that these granules have any connection with the neutrophile granules, 
since they exist in all polynuclear cells, and stages transitional to neutrophile 
granules apparently do not exist. 

Sherrington^ finds that in shed blood the nuclei of polynuclear leucocytes 
may reassume the spheroidal form, but it is to be doubted if this change ever 
occurs in the circulating blood. 

4. Eosinophile leucocytes vary in size from that of lymphocytes to 
that of polynuclear leucocytes. Their protoplasm contains large 
strongly acidophile granules which are believed to be integral 
parts of a cytoreticulum (Heidenhain, Gulland). Their nuclei are 
coarsely reticulated and usually bilobed, the lobes are more often 
separate than in the neutrophile cells, and they stain rather faintly 
with nuclear dyes. 

5. Mast-cells are mononuclear or polynuclear cells of different 
sizes, whose characteristic feature is the presence of large and small 
strongly basophile granules. These granules do not reflect the pure 
color of many stains, but are metachromatic^ especially with thionin. 
A few mast-cells are always to be found in normal blood, but when 
present in any considerable numbers they are pathognomonic of 
myelogenous leukemia. (Plate XL) Levaditi describes small 
acidophile granules in mast-cells. The mast-cell of the blood is 
entirely different in appearance from the mast-cell of the tissues. 

Leucocytes in Pathological Blood. Besides the above forms of 
colorless cells which alone are present in normal blood, other types 
of cells are seen in the circulation in disease. 

Myelocytes are mononuclear cells with neutrophile or with eosino- 
phile granules. Three types of myelocytes should be distinguished : 

(a) Ehrlich's myelocyte is a medium-sized cell with pale, 
usually central nucleus, and neutrophile granules. It is found in 
many morbid conditions, especially in leukemia and secondary 
anemia. (Plate VIII.) Ehrlich has described as " neutrophile 
pseudolymphocytes " very small myelocytes with densely staining 
nuclei, which were seen in hemorrhagic smallpox. 

(6) Cornil's myelocyte is a large cell, much larger than a poly- 
nuclear leucocyte, with pale eccentric nucleus and neutrophile 
granules. It is found almost exclusively in myelogenous leukemia, 
and less frequently in v. Jaksch's anemia. (Plate YIII.) 

(c) Eosinophile myelocytes may resemble the eosinophile cells 
of normal blood, except that their nuclei are single. Such cells are 
abundant in myelogenous leukemia, occur not infrequently in v. 
Jaksch's anemia, and have been found in myxedema by Mendel, in 
some infectious diseases by Turck, and in pernicious malaria by 
Bignami. Or, their granules may be of excessive size, in which case 



126 GENERAL PHYSIOLOG Y AND PATHOLOGY. 

they are pathognomonic of myelogenous leukemia. (Plate VIII.) 
Most myelocytes possess true acidophile nucleoli (Jolly). 

The Classification of Leucocytes. Although the leucocytes 
were discovered by Nasse in 1835, the first scheme of classification 
based upon their supposed points of origin was offered by Yirchow, 
who divided the colorless cells into lymphocytes derived from the 
lymph nodes, splenocytes from the spleen, while poly nuclear cells he 
regarded as developmental forms of the mononuclear. Similarly, 
Einhorn, a pupil of Ehrlich, classed the leucocytes as : (1) lympho- 
cytes, small and large, derived from the lymph nodes ; (2) myelog- 
enous cells (eosinophiles) from the marrow, and (3) large mononuclear, 
transitional, and poly nuclear cells, from spleen or marrow. 

In 1865 M. Schultze described the leucocytes as (1) non-granular 
(large and small mononuclears) ; (2) finely granular (neutrophiles), 
and (3) coarsely granular (eosinophiles and mast-cells). He believed 
that all granules and cells represent developmental forms of one series. 

Lowit's classification, based on the morphology of the nucleus, 
included small and large mononuclear cells (lymphocytes), " transi- 
tional '^ leucocytes, and polynuclear leucocytes. Regarding solely 
the nucleus, Lowit found no difficulty in deriving all leucocytes in 
one series of cells. It remained for Ehrlich to establish the essential 
distinction between leucocytes by demonstrating specific microchem- 
ical reactions in the granules of Schultze. 

Ehrlich divided the aniline dyes into three main groups : (1) 
Basic dyes, as hematoxylon, methylene blue, thionin, etc., act as 
bases, uniting, with selective power in the order named, with the 
acid principles of cells (nucleinic acid). (2) Acid dyes, as eosin, 
fuchsine, aurantia, act as acids, and unite with the basic principles 
of cells. (3) Neutral dyes. ■ When certain basic and acid dyes are 
mixed a compound is formed of modified staining qualities which 
unites with certain cell structures not readily stained by other 
methods. Such a mixture Ehrlich calls a neutropMle stain, an 
example of which is the triacid mixture. Neutral red seems also to 
fall in this class. 

According to their reactions to these dyes the granules of leuco- 
cytes in human blood may be divided into three main groups, baso- 
phile, acidophile (oxyphile), and neutrophile, and on these grounds 
the present classification of leucocytes is based, as follows : 

1. Basophile Cells : Mast-cells [^-granules). Granules strongly 
basophile. Lymphocytes. Protoplasm strongly basophile. Large 
MONON^ucLEAR LEUCOCYTES. Protoplasm slightly basophile. 

2. Neutrophile Cells : Polynuclear leucocytes. Neutrophile 
{e) granules. Myelocytes. Neutrophile granules. 

3. Eosinophile Cells : Eosinophile leucocytes. Large acido- 
phile granules {o-granules). Eosinophile myelocytes. Large 
acidophile granules. 

Ehrlich also described /3-granules which are amphophile, stain by 
both basic and acid dyes, and are found in some marrow cells, and 
^-granules which are small basophile granules said to occur in some 
mononuclear cells. 



PLATE IIL 




Normal Blood. (Fixed in Alcohol. Stained two hours by the 
Noeht-Romano^ATsky Method.) 



Fig. 1. Ameboid lympliocyte. From a case of malaria, blood on warm Rtage under a cover- 
glass twenty minutes. 

Fig. 2. Lympliocyte with large granules. 

Fig. 3. Large lymphocj^te ^dth ^aolet-stained c^^oreticulum, large and small granules, and baso- 
phile cell border. Bud-like pseudopod. 

Fig. 4. Ameboid large hrniphoc^'le. 

Fig. 5. Polynuclear leucoc^'te with c^d:o^eticulum and scanty granules. 

Fig. 6. Polynuclear leucocyte with numerous granules. 

Fig. 7. Group of blood plates. 

Fig. 8. Blood plates forming in red cell. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 127 

It is impossible here to consider all the objectioDs raised against 
the specific quality of the reactions demonstrated by Ehrlich, and 
especially the limitations shown to exist in the application of his 
principles to other tissue cells. At present it must be admitted that 
while there are rather narrow limits between which the reactions of 
granules may vary, yet each class of granules is peculiar to one cell, 
and transitional stages have not been demonstrated, while the sepa- 
ration of leucocytes according to the chemical character of their 
protoplasm is a much more exact classification than one on any other 
basis. While the original views attributed to Ehrlich have suffered 
considerable modification since it became evident that the granules 
of many tissue cells, though of variable composition, may give identi- 
cal reactions to dyes, and that the granules of the same leucocytes 
may stain differently, yet the wisdom of his classification is shown 
by the evidence which has accumulated regarding the significance of 
these granules. 

The classification and nomenclature of Kanthack and Hardy is 
often employed in the discussion of leucocytes. These authors 
describe (1) lymphocytes ; (2) hyaline cells, which are the large 
mononuclear leucocytes of Ehrlich, which cells, however, usually 
contain the granules described above ; (3) finely granular oxyphile 
cells, which are the neutrophile and amphophile leucocytes of 
Ehrlich ; (4) coarsely granular oxyphile cells, or eosinophile leuco- 
cytes ; (5) coarsely and finely granular basophile cells, which are the 
mast-cells. 

. Finer Structure of Leucocytes. Kecent studies have consider- 
ably increased the knowledge of the minute structure of leucocytes. 

For many years opinions have been at variance regarding the 
structure of the protoplasm of basophilic cells. It is now evident 
that the bodies of these cells, while showing the reticular structure 
of ordinary protoplasm, with fine nodal thickenings, also contain a 
special variety of granules. The nodal thickenings do not, however, 
have the sharp character of the other granules of leucocytes. It 
has been shown by Arnold, Gulland, and others, that the neutro- 
phile and eosinophile granules are connected by threads with the 
reticulum of their cells, and are thus integral parts of this reticulum 
(plasmatic). 

Under suitable conditions, in thinly spread, rapidly dried, densely 
stained cells, it is apparent that the cytoreticulum of large mononu- 
clear, neutrophile, and eosinophile cells is directly continuous with 
the nuclear network and that the clear space sometimes appearing 
to separate nucleus from body is artificial (Gulland). 

Ceritrosomes have been demonstrated in the leucocytes of lower 
vertebrates by Flemming, Arnold, Van der Stricht, Hermann, 
Heidenhain, and in human blood cells by Gulland and Levaditi. 
These bodies show no special affinity for any dyes, but are best 
demonstrated by basic stains. They have been stained by safranin 
and gentian violet (Flemming) and by methylene blue (Gulland). 
In human blood they are extremely minute, and their demonstration 
appears to be a very uncertain undertaking. 



128 GENERAL PHYSIOL OGY AND PA THOL OGY. 

Significance of Cell- granules. The theory of the higher significance of cell 
granules was first clearly stated by Altmann, although it was suggested by 
Ehrlich in his early studies of the granules of leucocytes. Instead of being 
degenerative or excretory products it is now apparent that they are a secretory 
product, and represent the centre of the specific function of the cell. 

Strong evidence in favor of this view was furnished in the demonstrations 
by Heidenhain, Arnold, GuUand, and others, that the granules are not para- 
plastic — that is, loose particles separate Irom the cytoreticulum, like fat, 
melanin, etc., but are plasmatic— i. e., integral parts of the cytoreticulum. 
The specific quality of the granules is also indicated by their chemical and 
tinctorial reactions. The differential chemical characters of the neutrophile 
and eosinophile granules will be considered later. (See Chapter V.) Although 
the granules of every cell of the same type may not all stain exactly alike, 
yet when submitted to fine chemical tests one cell is found to contain only one 
kind of granule. The studies of Knoll, Hirschfeld, Kurlofi", Gruneberg, 
Rawitz, and Hesse, upon the leucocytes of lower animals have shown that the 
wandering cells of vertebrates and invertebrates possess granules which are 
peculiar to each animal, and are strictly limited to separate types of cells. 
Ehrlich regards the opposite behavior of different cells under different chemo- 
tactic influences as evidence of the specific nature and function of each variety 
of leucocyte and of its peculiar granule. 

While the above considerations point to the secretory nature of the granules, 
the exact function of the secretion has not been demonstrated. Altmann 
believes that they furnish oxygen for the metabolic processes of the cell. 
Ehrlich once (1891) regarded them as a sort of reserve material destined for 
use within the cell, but has not expressed himself recently on this point. 
Hankin,^ Kanthack, Hardy, and Keng, apply the term afermes to the secretory 
granules of leucocytes, and believe that they are destined to be thrown out 
into plasma or lymph and to exert a bactericidal or antitoxic influence. Sher- 
rington and most olDservers cannot find sufficient ground for the acceptance of 
this view. Metchnikoff ^ refers to the granules as reserve material, but does 
not point out their exact destination. 

Arnold^ has gathered much interesting evidence regarding the 
origin and significance of cell granules^ some of which speaks against 
their specific quality and constant character, and, therefore, against 
the plan of classification of Ehrlich. Arnold finds that fat and 
hemosiderin may be absorbed by leucocytes and assume the same 
plasmatic position as the cell granules. He claims that under some 
conditions the neutrophile or eosinophile granules may become trans- 
formed into fat or hemosiderin. In his studies of the marrow cells 
he emphasizes the changeable character of the granules of leucocytes 
and the very common occurrence of more than one kind of granule 
in the same cell. 

Numbers of Leucocytes. The first estimates of the number of 
leucocytes in the cubic millimetre of blood were made by Samuel and 
Welcker and were generally accepted for some years. Malassez, 
with his improved method, considerably reduced these older figures. 
With the introduction of Thoma's instrument still more accurate 
estimates were secured which remain undisturbed at the present time, 
and agree fully with the more recent results obtained by Eieder, 
Reinert, and Limbeck. 

The following table is compiled from the chief contributions on 
this point : 



THE LEUCOCYTES AXD LEUCOCYTOSIS. 



129 



Obseryatioxs on Normal Numbers of Leucocytes. 



Samuel 

Welcker 

Moleschott . 

Malassez2 . 

Duperie 

Hayem 

Bouchout, Dubrisay 

Grancher . 

Hirt . 

Thoma, Lyon 

Hal la . 

Tumas 

Sorensen . 

Patrjgeon . 

Reinecke . 

V. Jaksch . 

Limbeck 

f adults 
I children 

'6 A.M. 
4 P.M. 



Rieder 



Reinert 



Average. 


Maximum. 


Minimum 


14,000 






13,432 


14,925 


12,857 




14,000 


12,605 





7,692 


3,750 


4,545 






6,000 






6,116 








9,000 


3,000 


f 8,388 
15,464 


10.590 


6,784 


7,066 


4,430 


7,533 


10,106 


4,960 


6,200 


9,600 
10 


4,800 




10,000 


2,000 


7,351 






7,482 






8-9,000 






7,680 


9,600 


4,200 


9,960 


12,400 


7,200 


5,125 






8,262 







In estimating the leucocytes in both health and disease one is con- 
fronted by a great Yariety of disturbing factors, including the causes 
of distinct physiological leucocytosis, the individual peculiarities of 
the subject, and the ordinary variations in the local condition of the 
part from which the blood is taken. All that has been said regard- 
ing accidental variations in red cells applies equally to leucocytes, 
and one must carefully consider the effects of vasomotor phenomena, 
of changes in the volume of plasma, and of the presence of inflam- 
mation or edema. It should be remembered that while the leuco- 
cytes remain nearly uniform in the great vessels their proportions in 
the capillary circulation may change more rapidly than those of the 
red cells, owing probably to chemotactic influences. The most 
common sources of error may be avoided by taking specimens about 
four hours after a meal and at the same hour each day. 

Proportions of Various Forms of Leucocytes. The proportions 
of the different forms of leucocytes in normal blood are even less 
fixed than their numbers. Ehrlich^s figures may well serve as a. 
standard for healthy adults. 

Lymphocytes, 22 to 25 per cent. 

Large mois^onuclear and transitional leucocytes, 2 to 4 
per cent. 

POLY^NUCLEAR NEUTROPHILE LEUCOCYTES, 70 tO 72 per cent. 

EosiNOPHiLE CELLS, 2 to 4 per cent. 

Mast-cells, 0.5 to 2 per cent. 

The chief variations from these limits which deserve mention are 
the maximum percentages given by Rieder for lymphocytes (30 per 
cent.) and by Limbeck for polynuclear leucocytes (80 per cent.). In 
childhood the proportion of lymphocytes is usually much increased 
(55 to QQ per cent.), and that of polynuclear cells correspondingly 
diminished (28 to 40 per cent.). (Gundobin, Rieder.) 



130 GEXEEAL PHYSIOL OGY AXB FA THOL G Y. 

Degenerative Changes in Leucocytes. 

While degenerative changes in leucocytes have always been recog- 
nized as necessary processes in degenerating tissue in which the 
leucocytes were lodged, references to acute degenerative changes in 
leucocytes of the circulating blood have been so scanty as to lead some 
writers to deny their existence. It, therefore, becomes necessary to 
consider briefly the general evidence at hand concerning the occur- 
rence and significance of such changes in circulating leucocytes. 

It was perhaps Lowit's claim that leucocytolysis necessarily pre- 
cedes leucocytosis, which called special attention in recent years to 
the destruction of leucocytes in the circulation. Although Lowit's 
claim cannot be fully supported, the fact that the majority of ]euco- 
cytoses are preceded or accompanied by the destruction of many 
leucocytes in the circulation has been amply proven by the work of 
Uskoff, Botkin, Gabritschewsky,^^ Engel, Klein, Goldscheider and 
Jacob, and many others. 

E. Botkin followed up the subject in a series of experimental and 
clinical studies and showed that in 1 per cent, solution of peptone 
and in the fresh plasma of various infectious diseases, all leucocytes 
dissolve and disappear with varying rapidity. The lymphocytes 
proved most resistant. The changes described by Botkin were of 
an extensive variety, but the principal features included the forma- 
tion of coarse granules in mononuclear cells ; extrusion and loss of 
grannies from polynuclear cells ; formation of vacuoles and clefts ; 
fragmentation and solution of cell bodies ; formation of blood plates ; 
swelling, fading, shrinkage, subdivision and final disappearance of 
nuclei. Comparing these experimental changes with those observed 
by himself or reported by others in infectious diseases and in 
leukemia, Botkin declared that no examination of the blood can be 
considered complete which leaves out of account the degenerative changes 
in leucocytes. 

The principal contributions which seemed then (1896) to justify 
Botkin's claim were those of Hankin, who found in the extrusiou 
and loss of granules of the rabbit's leucocytes the source of bac- 
tericidal alexines ; of Haetaguroff, who observed various degenera- 
tive changes in the leucocytes of typhoid fever ; of Engel, who 
described a variety of changes in the leucocytes of an anemic child, 
and of Gumprecht, who called special attention to the pathological 
changes in the leucocytes of leukemia. 

In 1895 the writer described degenerative changes in the leuco- 
cytes of diphtheria. Similar lesions have since been reported by 
File, who regarded many of the altered cells as dead, and by many 
others. 

In the absence of more extended observation it seems best to 
merely describe rather than attempt to accurately classify the 
pathological changes in leucocytes, yet a tentative classification may 
be employed for convenience sake. 

Acute' Degeneration of Leucocytes. This process is best 
demonstrated in acute infectious diseases, especially in severe cases. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 131 

As seen in diphtheria the aUerations affect both body and 
nucleus. 

In diphtheria the writer believed he could detect an increased 
acidophile staining tendency in the neutrophile granules^ a conclusion 
which he is disposed to retain, seeing that Kanthack had previously 
found that the pseudoeosinophile granules of the rabbit may be made 
to show increased acidophile tendency and higher refractive quality 
by the injection of minimum immunizing doses of microbic poisons. 
This observation, however, has not been further confirmed. That 
this change when it occurs belongs in the degenerative series is not 
clear, but it may be seen in cells Avhich show other distinct signs of 
degeneration. 

Diminution in the number of neutrophile granules is commonly 
observed in the polynuclear cells in acute leucocytosis. This 
abnormalitv may progress until very few granules are Jeft, but their 
complete absence is seen principally in chronic leukemia. It is 
usually associated with marked nuclear changes. Eosinophile cells 
may be similarly altered. Arneth has described cases of pernicious 
anemia and leukemia in which very few of the polynuclear leucocytes 
or myelocytes showed granules. 

Swelling and fragmentation of the bodies of leucocytes is commonly 
observed in acute leucocytoses. It is probable that many of the 
torn and distorted cells seen in dry preparations have undergone 
degenerative changes which have favored their complete destruction 
in smearing. These cells have been described as " leucocyte shadows " 
(Klein), a term well suited to recall their torn bodies, scattered 
granules, and faded nuclei. 

The reticulum of large and small mononuclear cells in leukemia 
and in severe acute toxemia may grow coarse?' and at times granidar. 
Botkin has described the appearance of granules in the dissolving 
lymphocytes of shed blood. Some of the lymphocytes of leukemia 
appear to be distinctly granular. Ehrlich depicts the separation of 
small peripheral fragments of the protoplasm of lymphocytes. Glob- 
ular projections from such cells are frequently encountered, but 
it does not appear certain that they represent degenerative plas- 
moschisis. 

Nuclear changes appear to be the most significant of the lesions of 
acute degeneration of leucocytes. In fresh or dried specimens the 
nuclei stain less densely with basic dyes, their outlines are irregular 
and the lobes shrunken. The degeneration may follow the type of 
karyolysis, with swelling and loss of chromatin, or of karyorrhexis 
with hyperchromatosis and subdivision of lobes (Gumprecht). In 
acute leucocytosis the former type is more usual, but in leukemia 
the latter form is abundantly seen. (See Plate X.) While the 
lobes of the normal polynuclear leucocytes are almost invariably con- 
nected with a thread of chromatin, many of the cells in severe acute 
leucocytosis show complete subdivision into three to six separate 
segments. 

Chronic Degeneration of Leucocytes. In diseases like leu- 
kemia in which peculiar chronic changes in white cells are promi- 



132 GENEBA L PH YSIOL OGY AND PA THOL OGY. 

nent, many of the alterations commonly seen in acute degeneration 
are also present. Thus, in myelogenous leukemia one finds leucocytes 
showing loss of granules, presence of vacuoles, granules of glycogen, 
faded irregular nuclei, and distortion and fragmentation of cell 
bodies. Some of the cells in leukemic blood, however, exhibit changes 
which at least in their abundance are characteristic of the disease 
and which seem certainly to be the result of chronic processes. 

Complete loss of neutrophile granules may be observed in many 
cells, both polynuclear and mononuclear, in leukemia, less frequently 
in other conditions. The cell body remains slightly acidophile, 
while the nucleus commonly shows degenerative changes. (Plate X.) 

Complete subdivision of nuclei of polynuclear cells into six to ten 
hy perch romatic segments is a rather characteristic appearance in 
leukemic blood, and is usually associated with complete loss of 
granules. (Plate X.) 

Hydropic Degeneration. In fresh blood many leucocytes may 
be found whose nuclei are indistinct or invisible and whose bodies 
contain many large and small vacuoles bounded by homogeneous or 
granular reticulum. These disintegrating cells are specially abun- 
dant in malaria and leukemia. In malarial blood Avhen such cells 
are pigmented, the prominent vacuoles, opaque granules, and stream- 
ing movements common in dying protoplasm strongly suggest the 
appearance of vacuolated parasites. In stained specimens they are 
found to be composed of pale staining remnants of nuclei. (See 
Plate IX., Fig. 3.) 

Hydropic degeneration of nuclei is practically limited to some 
peculiar leucocytes, both mononuclear and polynuclear, of leukemia. 
(Plate X.) 

Fatty Degeneration. Fatty degeneration of leucocytes has often 
been referred to as a part of the changes in pathological blood. The 
writer has seen globules in leucocytes blackening with osmic acid in 
sections of blood in the vessels of fatty viscera, very rarely in circu- 
lating blood. The presence of these globules in leucocytes is not a 
certain indication that they have resulted from the altered albumin- 
ous constituents of the cell, nor does it necessarily indicate a degen- 
erative process, so that in the absence of further evidence the writer 
is unable to include this form of degeneration among those affecting 
white blood cells. Even when fat is abundant in the plasma the 
leucocytes are commonly free from it (Gumprecht). 

Arnold^ describes in the leucocytes of the frog plasmatic and para- 
plastic granules of fat which were absorbed or englobed from the 
circulating medium. 

Glycogenic degeneration has been considered in Chapter II. 

Perinuclear Basophilia. In 1894 Xeusser (and later Kolisch) 
described the appearance of basic staining granules about the nuclei 
of polynuclear and other leucocytes, which he termed as above and 
claimed to be a somewhat pathognomonic sign of the uric acid 
diathesis. At the time this observation was announced Lowit stated 
that perinuclear basophilia was an artifact which he had kept in 
mind for some ten years. Xevertheless, Xeusser's perinuclear baso- 



THE LE UCOC YTES AND LE UCO C YTOSIS. ] 33 

philia brought considerable notoriety to the Vienna school during 
several years. Its lack of clinical or pathological significance has 
been fully demonstrated, among others, by Futcher and by Simon. 

Blood Dust. Hemokonia. — The older histologists have rather uniformly 
described in normal plasma minute spheroidal or spindle-shaped bodies of 
undetermined origin (Bizzozero, Landois, Hayem). Recently, Miiller^ has 
drawn special attention to their occurrence, describing them as spheroidal, or 
dumb-bell, or spindle-shaped granules j,u to I/j. in diameter, and exhibiting 
active Brownian movements, but no locomotion. They are not fat, being 
insoluble in alcohol and ether and not stainable with osmic acid, and they 
appear to have no connection with the process of fibrin-formation. Their 
identity with the granules of leucocytes was considered by Miiller, and is 
claimed by Stokes and Wegefarth, who found them to increase in number as 
the specimen stood, and observed that in different animals their size varied 
with that of the granules of the leucocytes, Nicholls identifies them with 
leucocyte granules on microchemical reactions. Miiller found them unusually 
abundant in a case of Addison's disease, and scanty in starvation and cachexia, 
but no clinical significance has been demonstrated for them. If not derived 
from leucocytes, they may be in part the extruded contents of fragmenting 
red cells or precipitated albuminous particles from the plasma. 



LEUCOCYTOSIS. 

Nomenclature. An increase of leucocytes distinctly above normal 
limits is called leucocytosis. When the increase affects principally 
the polynuclear leucocytes, the condition is termed polynudear leuco- 
cytosis or simply leucocytosis. An increase of lymphocytes alone is 
called lymphocytosis. Sometimes several varieties of cells are found 
in increased numbers, when the term mixed leucocytosis is used. 
Eosinophilia is perhaps an aduiissible word to designate an increase 
of eosinophile cells. 

A distinct diminution of leucocytes is either so phrased or termed 
hypoleuGocytosis in contrast to hyperleucocytosis, which signifies an 
excess of cells. 

Classification of Leucocytoses. Eieder first employed the fol- 
lowing natural divisions of the subject : 

I. Physiological Leucocytoses. 
Leucocytosis of digestion. 
Leucocytosis of pregnancy, 
Leucocytosis of the newborn. 

II. Pathological Leucocytoses. 
Post-hemorrhagic leucocytosis. 
Cachectic leucocytosis. 
Antemortem leucocytosis. 
Inflammatory leucocytosis. 

Each variety of leucocytosis has a somewhat particular significance. 
That of the inflammatory type will first be considered. 

Significance of Inflammatory Leucocytosis. It was early seen 
that the most typical occurrence of transient leucocytosis is limited 
to certain acute infectious diseases, and here its significance has been 
the subject of much study and discussion, the extent of which has 
shown this subject to be one of the broadest of biological problems. 



134 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 

A very simple illustration of a principle believed to exert prominent influ- 
ence in the behavior of leucocytes is found in the actions of certain myxo- 
mycetes in the presence of chemicals. Stahl found that Ethalium septicum 
placed on a moistened surface close to a drop of infusion of oak bark moved 
actively toward and into the infusion, but moved actively away from a solu- 
tion (5 per cent.) of glucose. He also noted that the plasmodium of Fuligo, 
which at first moves away from a 2 per cent, solution of salt, will later, if 
needing water, advance and enter the solution. Pfeiifer called this varying 
sensitiveness of protozoa toward chemicals chemotaxis, and the above observa- 
tions may serve to illustrate positive and negative chemotaxis and the trans- 
formation of a negative into a positive chemotaxis. PfeifFer also extended 
these observations to bacteria, finding that nearly all nutritive substances 
exert a positive attraction for bacteria, which is determined not by move- 
ments of diffusion of the liquids, but by the specific nature of the chemical 
substances. 

A chemotactic influence of bacteria upon leucocytes apart from the phago- 
cytic tendencies of MetchnikofF was pointed out by Peckelharing, among the 
first, who inserted beneath the skin of frogs pieces of parchment containing 
anthrax, and found them after some hours surrounded by leucocytes. Gabrit- 
schewsky^ showed that the attractive agent was dissolved in the fluids of these 
cultures. An extensive mass of observations has accumulated, showing that 
there is a wide variety of bacteria and bacterial and chemical products which 
exert a specific positive attraction upon leucocytes. In some instances a pre- 
liminary repulsion is succeeded by a positive chemotaxis, but the examples of 
distinct negative chemotaxis of bacteria upon leucocytes are so uncertain as 
to lead Kanthack to conclude that probably no bacteria actually repel leuco- 
cytes, though some very rapidly destroy the attracted cells, so that the sur- 
rounding area is comparatively free from them. An apparently clear example 
of negative chemotaxis is found in the action of the bacillus of chicken 
cholera in some susceptible animals, while there are a great many examples of 
failure of positive chemotaxis {Bacillus tuberculosis, typhosus.) 

A distinctly new element was added to the knowledge of chemotaxis when 
it was first clearly shown, by Leber,^ that chemotactic action of bacteria is 
exerted upon leucocytes at a distance. On placing within the anterior chamber 
of the eye of the rabbit a fine tube filled with a substance extracted from cul- 
tures of Staphylococcus aureus, Leber found that the leucocytes would promptly 
overcome the action of gravity and force a way for a considerable distance 
through lymph channels in order to enter the tube. 

The subject was again considerably enlarged in the experimental produc- 
tion of leucocytosis by Limbeck, who pointed out that along with the local 
afflux of leucocytes following subcutaneous injections of bacterial cultures, 
there is a marked increase in the general circulation, which in fact precedes 
the local changes. 

This action upon distant blood-producing organs causing an outpour of 
leucocytes has been variously interpreted. It has been referred by most 
authors to the direct chemotactic action of the virus distributed through the 
circulation. Limbeck regarded the intravascular leucocytosis as somewhat 
in the nature of a forerunner and integral part of the purulent exudate which 
gathers at the point of inoculation. Weiss carries this idea still further, 
actively maintaining that leucocytes in inflammatory conditions are formed 
in various tissues whence they pass into the blood. Leucocytosis is, therefore, 
not of uniform significance and origin, but is the expression of various under- 
lying tissue changes in disease. Lowit believed that the increase of leucocytes 
merely represents a regenerative effort on the part of the marrow to replace 
destroyed leucocytes, his observations supporting Virchow's original view of 
the origin of leucocytosis. Buchner and Romer also refer leucocytosis solely 
to the increased production of the cells under the stimulus of bacterial proteins. 
That an increased floiv of lymph occurs in many cases of inflammatory leucocy- 
tosis, especially in that in which the lymphocytes are increased, is indicated 
by the demonstration of a special lymphogogic property in bacterial proteins 
(Buchner, Gartner, and Romer). 

Schultze, Rieder, and Goldscheider and Jacob, have held more or less strictly 



THE LEUCOCYTES AND LEUCOCYTOSIS. 135 

to the opinion that the leucocytes are not greatly multiplied during leucocy- 
tosis, but, on the contrary, are merely overabundant in peripheral vessels, or to 
a moderate extent are drawn into the circulation from the depots of ready- 
formed cells in the marrow. 

It is impossible here to consider in detail the basis of these various 
hypotheses. Of the last mentioned it must be said that there is 
abundant evidence both of a new production of leucocytes in the 
viscera and of an increased outpour of these cells during leucocytosis. 

Although the evidences of new formation of leucocytes in the circu- 
lating bloody lymph nodes, and marrow, found by Schmidt, Lowit, 
and Rieder, seem to them inadequate to account for a great increase 
in the number of these cells, this result may be referred to the 
uncertainty regarding the origin of leucocytes, to the mistaken 
opinion that poly nuclear leucocytes are derived from lymphocytes, 
and to the difficulty of demonstrating early proliferative changes in 
such widely distributed fields as the blood and marrow. Yet Lowit^ 
could find considerably increased numbers of mitotic and amitotic 
nuclei in circulating leucocytes during leucocytosis. 

Recent studies of the marrow during experimental leucocytoses 
have fully established the existence of greatly increased cellular 
proliferation beginning in the early stages of leucocytosis, and, in 
prolonged cases, completely transforming the histological appearance 
of this tissue. The writer in 1895 compared the marrow of typhoid 
fever with that of pneumonia and other exudative diseases in a series 
of cases, and found a very striking difference in the pulp cords in 
the two conditions, leucocytosis being accompanied by marked cel- 
lular hyperplasia, affecting principally the neutrophile myelocytes. 

Rogers and Josue found, forty-eight hours after the injection of 
staphi/lococGus aureus into rabbits, marked congestion and cellular 
hyperplasia of the marrow cords affecting principally the nucleated 
red cells and eosinophiles, but by the third day these cells disap- 
peared, and neutrophile myelocytes with many giant cells formed 
the bulk of the noAv greatly hypertrophied cords. These observa- 
tions have been verified and extended by Muir and many others. 

The sole ground that remains to those who deny that inflammatory 
leucocytosis is essentially a new formation of leucocytes is the proba- 
bility that many leucocytes drawn into the circulation during the 
first hours of leucocytosis are ready-formed in the marrow. 

Of the other hypotheses it still appears that each contributes a 
portion of the truth. Probably the combined influences of chemo- 
taxis, and of the new formation of leucocytes stimulated by bacterial 
proteins, etc., are chiefly responsible for the general afflux of white 
cells. The destruction of leucocytes has repeatedly been shown to be 
a subordinate factor and entirely too slight to stimulate the produc- 
tion of new cells through ordinary channels, as suggested by Lowit. 

Limbeck's early belief in a close connection between local exudate 
and general leucocytosis is at least partially true, and serves to 
emphasize, as Grawitz points out, that many tissues, to an extent, 
and not merely the blood-forming organs, furnish leucocytes to the 
circulation. 



136 GENERAL PHYSIOLOGY AND PATHOLOGY. 

In so far as chemotactic influences are concerned in leucocytosis 
it should be remembered that the essential nature of the attractive 
force remains entirely unknown. 

In studies upon the visceral changes in leucocytosis the writer 
became convinced that some phenomena now attributed to an obscure 
chemotactic influence may be fully explained on purely mechanical 
principles. This statement applies especially to the sifting of 
cohesive leucocytes by swollen capillary endothelium, and to a less 
extent to the outpour of new-formed leucocytes from the marrow, 
but in the phenomena of local exudates other factors seem undoubtedly 
to be concerned. 

The Course of Leucocytosis. The experimental study of leuco- 
cytosis has greatly increased the knowledge of the order and signifi- 
cance of the phenomena connected therewith. It was first observed 
by Werigo that the inoculation of animals with bacterial cultures 
is followed within five or ten minutes by a pronounced diminution 
of circulating leucocytes (hypoleiccocytosis), by the deposit of the bac- 
teria in the capillaries of the lungs, liver, and other viscera, and by 
their complete disappearance from the blood. 

Approaching the subject from another standpoint, Goldscheider 
and Jacob, and the writer, found that along with the deposit of bac- 
teria the leucocytes are also sifted out of the circulation and perma- 
nently lodged in visceral capillaries, principally in the lungs and 
liver. The writer also partially agreed with Lowit that actual 
destruction of leucocytes follows such intravascular inoculations, 
especially with large doses, but did not find, contrary to Lowit, that 
leucocytolysis in disease plays more than a very subordinate part in 
ridding the blood of white cells. The initial hypoleucocytosis has 
been observed very constantly to precede the appearance of leuco- 
cytes in increased numbers, and the same phenomenon has been 
observed in the course of many natural infections in the human 
subject. 

In experimental studies it has been found that many animals 
perish during the stage of hypoleucocytosis, especially when an 
active virus is introduced into a susceptible animal. Thus the inocu- 
lation of guinea-pigs with virulent cultures of diphtheria is followed 
by death within twenty-four to forty-eight hours, during persistent 
hypoleucocytosis, while in the less susceptible rabbit the same treat- 
ment usually kills the animal, but not before leucocytosis has become 
well established. In general, the increase of leucocytes follows the 
initial diminution more rapidly in those animals in which the course of 
the infection is more favorable. The same rule is found to hold in 
the human subject, initial hypoleucocytosis, sometimes persistent, 
having been observed in malignant cases of pneumonia (Kikodse and 
others), diphtheria (Billings), septicemia, etc., and its unfavorable 
import in these diseases has been fully demonstrated. 

In infections of ordinary virulence hypoleucocytosis is established 
within one-half to two hours after the initial diminution, and Gold- 
scheider and Jacob succeeded in exciting pronounced leucocytosis 
without any demonstrable initial decrease in cells. During the 



THE LEUCOCYTES AND LEUCOGYTOSIS. 137 

course of febrile reaction to exudative processes, and sometimes 
during a considerable period thereafter, hyperleucocytosis persists. 
The grade of leucocytosis has been found to vary often with the height 
of the temperature, more closely with the extent of the exudate, but as 
might be expected from its recognized significance, measures more exactly 
the reaction of the system to the infectious agent 

Throughout the stages of inflamuiatory leucocytosis it is the poly- 
nuclear leucocytes which are chiefly or exclusively concerned with 
the process. During hypoleucocytosis these cells, and as the writer 
finds, the large mononuclear cells, are greatly reduced, having been 
caught in the capillaries, while the lymphocytes remain in large 
proportion. Tery soon, with the increase in total numbers, the 
polynuclear cells are found in excessive proportions (80 to 95 per 
cent.), and even when the total increase is not great the excess of 
polynuclear cells is so constant as to furnish at times significant 
information regarding the character of the infection. 

The hyperemia and excitation of the marrow is indicated by the 
presence of normoblasts (Timofjewsky) and of a few myelocytes 
which have now been found in many severe leucocytoses, especially 
in diphtheria (Engel). 

An absolute increase of lymphocytes, sometimes of extreme grade, 
as observed by the writer in diphtheria, is often noted in the course 
of inflammatory leucocytosis, and is to be referred to special involve- 
ment of lymphoid tissues. 

Ehrlich^ holds that while polynuclear leucocytosis is referable to 
chemotactic influences acting from a distance, lymphocytosis is 
always the result of local irritation acting mechanically. The recent 
observations on the ameboid properties of lymphocytes and large 
mononuclear leucocytes indicate, however, that these cells may 
actively respond to certain chemotactic influences and emigrate from 
the vessels, and they have been described as passing through vessel 
walls in nephritis, through squamous epithelium in tonsillitis, and 
gathering in large numbers in the early stages of abscess formation 
(Janowsky). On the other hand, Marchand's conclusions, that these 
round cells in iuflammation are chiefly derivatives of fixed tissue 
cells or of extravascular lymphocytes, represent the old and con- 
servative opinion on this subject. 

Relative or absolute lymphocytosis is seen in digestion leucocytosis 
(Rieder), in typhoid fever, with tumors of bone, and, in general, is 
a frequent feature of inflammatory leucocytosis in children. 

During the subsidence of acute leucocytosis the neutrophile are 
sometimes replaced by a considerable proportion of eosinophile 
cells, as in pneumonia, septic processes, etc. The cause of this phe- 
nomenon is undetermined, but it has been shown to be of favorable 
import. 

The behavior of the different cells in leucocytosis is largely in 
accord with their known characteristics elsewhere. The actively 
ameboid and phagocytic cells are chiefly affected, while the lympho- 
cytes are much less frequently disturbed. An exception to this rule 
is found in the actively ameboid eosinophile cells, but these are 



1 38 GENERAL PH YSIOL OGY AXD FA THOL QY. 

rarely found to sliow phagocytic qualities. The bearing of these 
facts upon the significance of leucocytosis will be considered later. 

Relation of Leucocytosis and Phagocytosis to Immunity. The 
studies of Metchnikoff upon phagocytosis in lower animals have not 
only established the great importance of this process as a protective 
measure in the protozoa, but have gone far to explain the significance 
of leucocytosis in the higher metazoa. There is no room to doubt 
that monads, for example, englobe, digest, and destroy living threads 
of leptothrix, and the steps through which Metchnikoff has traced 
the process seem to show that in animals as high as frogs the leuco- 
cytes alone are responsible for the englobement and destruction of 
anthrax bacilli. In the higher vertebrates, however, other factors 
may very well supervene, and before accepting the phagocytic doc- 
trine of leucocytosis in the haman subject it is necessary to consider 
in some detail the extent and limitations of the process in higher 
vertebrates. 

The process of phagocytosis, as described by Metchnikoff, begins with the 
chemotactic attraction of leucocytes toward bacteria, the englobement of the 
germs, often in the living virulent condition, and their digestion in stages 
which may be followed by changes in form and staining quality. The power 
to approach and englobe bacteria is obviously found in the ameboid activity 
of leucocytes. The power to digest bacteria is indicated by the morphological 
and chemical changes above mentioned, which indicate the breaking up of a 
bacillus into granules and its gradual loss of staining capacity. Moreover, a 
digestive ferment has been demonstrated in leucocytes by Eossbach and 
Leber,^ and many investigators, especially Buchner,'^ have demonstrated very 
high bactericidal power in exudates rich in pus. That leucocytes actually 
exert these bactericidal powers in infectious diseases is strongly indicated by 
the different behavior of these cells in refractory and susceptible animals. It 
has been repeatedly shown that the leucocytes of susceptible animals which do 
not naturally attack certain bacteria may be made to do so by the immuniza- 
tion of the animal, as in the infection of mice and guinea-pigs with anthrax, 
and pigeons and rabbits with chicken cholera. That the englobed bacteria 
are alive and active has been shown by their movements within the surround- 
ing vacuoles of the leucocytes, and by the subsequent development of the 
englobed bacteria when the leucocytes are placed in bouillon. {Anthrax in 
pigeons, Vib. Metch. in immune guinea-pigs.) Indeed, an increase in virulence 
has been found in cultures obtained from some bacteria passed through the 
leucocytes of refractory animals. Moreover, Lubarsch has shown that frogs' 
leucocytes are more actively attracted by living bacteria than by the same 
germ when dead. 

It should be noted that drugs which inhibit the activities of leucocytes have 
been found to greatly accelerate the spread of certain infections. {Opium in 
cholera, Cantacuzene.) 

The histological study of the reactive process at the seat of inoculation of a 
virus under various conditions has, also, furnished very strong support of the 
belief in the essential importance of phagocytosis. It has repeatedly been 
shown that in susceptible animals injections of highly virulent bacteria are, 
in general, followed by serous and bloody exudates which fail to limit the 
infection which becomes general and kills the animal, while the same treat- 
ment of immune animals is followed by highly purulent exudates, the limita- 
tion of the infection, and recovery (Gabritschewsky-^). 

Finally, the results of minute study of the behavior of various phagocytes 
should be considered. The two actively phagocytic leucocytes, the polynuclear 
neutrophile and large hyaline cells, do not attack all bacteria ia the same 
manner. The former are less selective, englobing nearly all forms of bacteria. 
Yet the bacillus of leprosy is found almost exclusively within the large hya- 



THE LEUCOCYTES AND LEUCOCYTOSIS. 139 

line cells which do not attack streptococci or gonococci. Kanthack and Hardy 
have made important observations in this field. Examining a hanging drop 
of frog's lymph inoculated with a few anthrax bacilli, they found that the 
eosinophile cells were first attracted to the bacilli, that they discharged their 
granules upon coming into contact with the germs, and that degenerative 
changes soon appeared in the bacteria. Liter the large hyaline cells sur- 
rounded the mass, the oxyphiles dropped away, and the altered bacteria were 
englobed and digested by the hyaline leucocytes. These observers found the 
same division of labor among leucocytes in various animals up to man, the 
hyaline cells acting as phagocytes of the celomic and lymphatic systems, and 
the finely granular oxyphile cells as phagocytes in the hemal systein. They 
ascribe important bactericidal functions to the granules of eosinophile leuco- 
cytes in preparing germs for englobement by the ameboid phagocytes. 
Hankin also came to identical conclusions regarding the importance of 
eosinophile cells in phagocytosis in the rabbit. 

Based upon these and many other similar observations, verified by 
many but actively combated by others, Metchnikoff concluded that 
phagocytosis is the essential feature of inflammation, and the chief 
mechanism in immunity, and gave exclusively to the leucocytes and the 
endothelial and other phagocytic tissue cells a function of vast impor- 
tance. 

It has been necessary, however, to modify the original claims of 
Metchnikoff in an important particular, that an extracellular influence 
is exerted upon bacteria which is sometimes a necessary preliminary to 
phagocytosis. 

The steps by which this fact has been demonstrated may be 
briefly indicated. 

Traube, Fodor, and others recognized that the destruction of bacteria in the 
living blood is often extremely active, and it was suggested that the fluid 
plasma, and not the leucocytes and endothelia, is the chief agent in freeing 
the animal organism from infectious germs. Grohman then demonstrated the 
bactericidal action of shed blood. Nuttall next found that during the process 
of inflammation, about the seat of inoculation in rabbits infected with attenu- 
ated anthrax, many bacteria which are not englobed nevertheless show degen- 
erative changes, and he also found that blood serum and lymph possess very 
active bactericidal powers. These observations were verified and greatly 
extended by Nissen, Hankin, Behring, Buchner, Prudden, and Vaughan, who 
have fully established the presence both of bactericidal and of antitoxic 
principles. 

It soon became apparent, however, that there exists a very close connection 
between these "defensive proteids " of blood and exudates, and the leuco- 
cytes. Hankin, Buchner, Kossel, and Vaughan have shown that a nucleo- 
proteid derived probably from the nuclei of leucocytes is the bactericidal 
agent in serum, exudates, and lymph. This bactericidal proteid belongs to^the 
class of enzymes, is extremely unstable, is destroyed by heating to 55° to 65° 0., 
and has been called by Buchner " alexine," and by Ehrlich " complernent.*' 

According to Hankin, blood serum ordinarily contains little of this agent, 
but after the second day of leucocytosis it is secreted by the eosinophile cells 
of rabbits' blood or is discharged from these cells during defibrination. 
Hahn and Van de Velde have shown rather conclusively that the alexines are 
a secretory product of the living leucocyte, and are not produced by the 
destruction of these cells, although they may be set free thereby. Hankin, 
Buchner,^ Hahn, Bordet, Schattenfroh, Bail, and others have established the 
essential relation between the bactericidal power of exudates and their content 
in leucocytes, and have placed this relation beyond doubt by such demonstra- 
tions as that of Denys and Havel, that the blood and exudates of dogs lose 
their bactericidal power when freed by filtration or the centrifuge from intact 
leucocytes, but regain this power when the leucocytes are replaced. 



140 GENERAL PHYSIOLOGY AXD PATHOLOGY. 

The controversy regarding the so-called ^' phenomenon of Pfeiffer ^^ has also 
ended in a way to favor the importance of leucocytes in the defence of the 
organism. PfeifFer found that when cholera cultures are injected into the peri- 
toneum of highly immunized guinea-pigs, the germs are broken up into gran- 
ules, and to some extent dissolved by the peritoneal fluid before leucocytosis 
and phagocytosis have become fully established, but not, as some citations of 
this work would lead one to suppose, before the leucocytes present are actively 
engaged in phagocytosis. 

MetchnikofF^ promptly repeated this experiment, finding that the cholera 
spirillum flourishes in a hanging drop of the same peritoneal fluid which in 
the body is bactericidal, that the peritoneal fluid is really very rich in leuco- 
cytes ; that if a great afflux of leucocytes is previously excited by injection of 
bouillon the phenomenon of Pfeiffer is suppressed, but the germs are englobed 
and destroyed just as quickly by the leucocytes ; and he found, in general, that 
the phenomenon of Pfeiffer occurs only in animals whose leucocytes possess 
very active bactericidal and phagocytic qualities, and only in those situations 
where leucocytes are or have been abundant. 

The discovery of the "phenomenon of PfeifFer" placed beyond question 
that bacteria may be destroyed by entirely extracellular processes, a fact now 
not infrequently illustrated in the dissolution of bacteria in Widal's test. 
While Metchnikoff" accepted this fact and altered his views as to the invaria- 
ble necessity of phagocytosis, the application of his doctrine was extended 
rather than narrowed ; for it still remains true that the bactericidal principles 
are elaborated principally in the leucocytes. 

Since the development of Ehrlich's theories of immunity Metchnikoff and 
his school have succeeded in reconciling to a very large extent their somewhat 
opposing views regarding the mechanism of immunity. 

In the destruction of bacteria Metchnikoff recognizes the interaction of two 
principles, immune body (fixator) and complement {alexine), but while admitting 
that the fixator circulates free in the plasma he claims that the alexine is lib- 
erated only on the destruction of leucocytes, and does not exist free in the 
plasma, while both are largely or exclusively the product of leucocytes. These 
conclusions have been reached by combining the morphological study of cells 
and tissues with the purely chemical observations of Ehrlich. 

Observations Indicating that the Alexine is Not Free in the Plasma. Several 
observers have found that red cells placed beneath the skin of animals immu- 
nized against these cells are not dissolved until leucocytes begin to gather 
about them. In guinea-pigs possessing spermatoxin the spermatozoa are not 
dissolved in the animals' testicles, although in the test tube these same sperma- 
tozoa are dissolved by the serum of the same animal. In immunized animals 
hemolysis in the peritoneum may be prevented by washing the peritoneum 
with salt solution, thereby removing the alexine. Levaditi found that hemo- 
lytic serum is inert when obtained by centrifuging blood in paraffined tubes 
which prevents destruction of leucocytes, while these same red cells, loaded 
with fixator, may afterward be dissolved by the addition of normal serum 
obtained in the ordinary way, and containing alexine from disintegrated leu- 
cocytes. Walker also has found that serum drawn immediately after coagu- 
lation of the blood is very deficient in hemolytic properties as compared with 
that drawn after six to eight hours. Besredka finds that anticomplement serum 
acts upon the leucocytes preventing phagocytosis. 

The chief action of the fixator (immune body) Metchnikoff believes to lie 
in stimulating phagocytosis, which is also facilitated by agglutination of 
bacteria or foreign cells. The chief source of the fixator he believes to be in 
a secretion from the leucocytes, and not from the specific cells aflTected by 
the immunization, since he obtained an active spermatoxic serum from a cas- 
trated animal. 

Macrocytase, Microcytase. Metchnikoff brings forward strong evidence to 
show that the large lymphocytes {macrophage.^) possess a different function 
in immunity from the poly nuclear leucocytes {micfrophages). 

Exudates rich in polynuclear leucocytes (microcytase) are actively bacteri- 
cidal, but not hemolytic, while exudates containing many macrophages 
(macrocytase) are actively hemolytic, but not bactericidal. Injections of red 



THE LEUCOCYTES AND LEVCOCYTOSIS. 141 

cells into the pleural cavity cause exudates rich in macrophages, while injec- 
tions of bacteria excite exudates rich in polynuclear cells, each of the exudates 
proving antagonistic only to the agents injected. 

On injecting cholera bacilli into the peritoneal cavity of an immune animal 
it was found that both macrophages and microphages englobed the bacteria, 
and while those within the microphages perished, those in the macrophages 
multiplied and destroyed these cells. From such observations MetchnikofF 
concludes that the macrophages act only on foreign body cells, and the micro- 
phages only on bacteria. 

That the macrophages are the chief producers of antitoxins he deduces from 
the fact, among others, that the alligator, whose leucocytes are almost exclu- 
sively macrophages, is a very active producer of antitoxins. 

The foregoing review of the steps through which the present con- 
ception of the relation of phagocytosis to immunity has been reached, 
while defective in important and highly interesting details has been 
rendered necessary in order to set in its proper light the significance 
of inflammatory leucocytosis. 

It is now apparent that leucocytosis repi^esents Nature^s attempt to 
rid the blood and the system, by means of leucocytes and theii' products, 
of the bacterial and toxic causes of disease. 

It is now possible, also, to understand the varying significance of 
hypoleucocytosis, and to place correct interpretations on the various 
grades of hyperleucocytosis in infectious diseases ; to trace the rela- 
tion between local and intravascular leucocytosis, and explain many 
of the phenomena of exudative inflammation ; to properly interpret 
the predominance of mononuclear, or of polynuclear, and, to some 
extent, of eosinophile cells, and to recognize the specific quality of 
the different varieties of leucocytes ; while the application of all 
these facts to questions in general pathology has been most extensive. 

Ehrlich's Theories of Immunity. 

The main contributions which have culminated in the partial 
acceptance of certain principles governing immunity now known as 
Ehrlich's side-chain theory have been : 

{a) The observation by Ehrlich that the neutralization of toxin by 
antitoxin does not follow the laws of fixed proportions. For exam- 
ple, if to a mixture containing 100 lethal doses of diphtheria toxin 
neutralized by antitoxin one adds several additional lethal doses 
this mixture still fails to kill the test animal (Ehrlich's phenomenon). 

{b) The observation by Bordet that hemolytic serum is inactivated 
by heat (55° to 65° C.) and may be reactivated by addition of 
normal fresh serum (demonstration of the " complement''). 

(c) The observation by Kraus that bactericidal sera precipitate 
albumins of bacterial cultures in addition to the agglutination and 
solution of the bacteria. 

These observations taken with what was previously known regard- 
ing the bactericidal action of blood serum and body fluids, and 
regarding agglutination of bacteria by specific sera, the phenomenon 
of Pfeiffer, and the behavior of leucocytes in infection, all exten- 
sively elaborated by a multitude of workers, have led to the present 



142 GENERAL PHYSIOLOGY AND PATHOLOGY. 

complex state of our knowledge of immunity. The full details of 
this work are at present most fully presented by Aschoff. 

Simultaneously with this line of progress it should not be forgotten 
that physiological chemistry proceeding along more or less estab- 
lished paths of the chemistry of intracellular ferments, and physical 
chemistry with its contributions on osmosis and electrolytic dissocia- 
tion, have built up a considerable fabric which may in some respects 
threaten the permanency of Ehrlich's theories. It is not to be sup- 
posed that there is only one way in which foreign cells and bacteria 
or their products can be destroyed in vitro or in the body. 

The reader who desires to follow the progress of studies on 
immunity requires a considerable knowledge of Ehrlich's theories 
and of the technical terms used by this school of workers. The 
following brief definitions and elementary explanations may tempo- 
rarily suffice for the purpose : 

Fig. 27. 




Types of receptors. R I-Order I., including antitoxins, anticomplements, antiamboceptors. 
an ti precipitins, etc. R Il-Order II., including toxins, complements, agglutinins, precipitins. 
R Ill-Order III., cytolysins, bacteriolysins, hemolysins, etc. B, receptors free from cell, called 
haptins. 

General Nature of Ehrlich's Theories. Ehrlich believes that 
the action upon foreign cells exerted by the various principles con- 
cerned in immunity is much like the absorption of food products by 
the cells. No toxic agent can affect a cell unless that cell possesses 
certain groups of molecules called receptors^ of which most cells pos- 
sess several varieties, with chemical affinities for the toxin. 

Moreover, when one of these receptors is occupied by a toxic 
molecule it is rendered useless to the cell and is soon replaced by 
new receptors of the same type, which develop in excess of the origi- 
nal requirements of the cell and tend to be thrown off as free recep- 
tors (haptins). 

From the study of the complex processes occurring in the reactions 
of immunity Ehrlich concludes that these cell receptors are of three 
types, designated as receptors of Orders I., II., III. (Fig. 27). 



THE LEUCOCYTES AND LEUCOCYTOSIS. 



143 



The simplest receptors, Order I., are the antitoxins, which consist 
of haptins possessing merely one bond of union which unites with 
the toxin. 

Other receptors, Order II., possess two special groups, a hapto- 
phore group uniting with the susceptible cell and a toxophore group 
producing some special action upon the affected molecule or foreign 
cell. The agglutinins and precipitins are such bodies. 

"Eeceptors of Order III. possess two bonds of union, one a hapto- 
phore group uniting with the cell, and a complementophore group 
uniting with the complement (described later) which is necessary to 
complete the action of this group of principles. The cytolysins 
belong to this order. 

Toxins. The toxins are bodies, like receptors of Order II., pos- 
sessing a stable haptophore group uniting with the receptors of suit-' 
able cells and a toxophore group which exerts the specific poisonous 
action upon the cell. 

Fig. 28. 




./ooo "^oo 

BacterialCell 

Development and action of toxins, agglutinins, precipitins. 1. Development from bacterial 
cell. 2. Free toxin, etc. 3. United to receptor of susceptible cell and active. 4. United to 
antitoxin and inert. 5. Toxophore group destroyed, as in the toxoid. 



Toxins are composed of various toxin molecules with varying 
degrees of affinity for antitoxin and various degrees of toxicity. 
When such toxins, in bulk, are incompletely saturated with antitoxin, 
the most active toxin molecules are first saturated, leaving less active 
molecules untouched. Such incompletely saturated toxins are called 
toxones and produce in animals modified toxic symptoms (late pareses 
in diphtheria). Bordet, however, offers another explanation of the 
nature of toxones. 

Toxins may, spontaneously or from a variety of procedures, lose 
many or all of their toxophore groups, without losing their hapto- 
phore groups or their capacity to unite with antitoxin. They are 
then called toxoids (Fig. 28). 

A toxin cannot unite with a cell which does not possess receptors 
with affinities for that toxin. Although most cells possess some 
receptors for all toxins, some cells have a great abundance of recep- 
tors for particular toxins. Thus, brain tissue of many animals 
absorbs many times as much tetanus toxin as does liver tissue. 



144 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



The mode of action of the toxophore group upon the cell is not 
understood, but resembles in many respects a fermentative process. 
All these combinations and actions require time. 

The haptophore group of toxins is usually unaffected by moderate 
heatj but the toxophore group, while not thermolabile, is less stable 
than the other and may be destroyed by many procedures not affect- 
ing the haptophore group. Immunization by toxones and toxoids, 
which possess unsaturated haptophore groups, has been demonstrated. 

Cytolysins, Hemolysins, Cytases. The destruction of bacterial and 
other foreign cells results from the interaction of two principles, the 
immune body [amboceptor, fixator, substance sensibitatrice) and the com- 
plement (alexine, addiment). 

The complement is derived principally from leucocytes, is present 
in all normal sera, and is destroyed by heating to 55° or 65° C. for 
one-half hour. There are, perhaps, thermostable complements. The 
complements, like receptors of Order IL, possess two groups, a hapto- 



FlG. 29. 



JICS 





Development and action of cytolytic agents. 1. Amboceptor developing from immuniz- 
ing cell. 2. Free amboceptor as in hemolytic serum. 3. Complement anchored to cell by 
amboceptor. 4. Complement anchored to amboceptor, but prevented from action on suseep* 
tible cell by antiamboceptor. 

phore group uniting with the immune body, and a toxophore group 
exerting destructive action on the attacked cell. Heat destroys the 
toxophore group, and heated complements are called complementoids. 
They may still combine wdth the immune body by their uninjured 
haptophore group. Although complement is present in normal serum, 
Ehrlich claims the existence of a multiplicity of complements in both 
normal and immune sera. Complements are less specific in their 
action than immune bodies. Thus the immune body of humanized 
rabbit serum — i. e., one which has been immunized to human blood — 
acts almost exclusively on human red cells, but the complement for 
such immune body may be supplied by a variety of sera. Yet for 
bacterial immune bodies some complements are much more active 
than others and some are entirely inert. The amboceptor (immune 
body) of cytolytic sera is derived from the cells against which the 
immunization is directed and from the leucocytes, and consists of the 
free receptors of these cells, receptors of Order III. For example. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 145 

the amboceptors of humanized rabbit serum consist of free receptors 
produced in excess and cast off into the serum from the red cells of 
the rabbit affected by the toxic influence of the injected human red 
cells. They are also produced by other cells which have to some 
extent the same receptors as the red cells. The amboceptors devel- 
oped in bactericidal serum are derived from tissue cells and espe- 
cially from the polynuclear leucocytes (Metchnikoff). The amboceptor 
resists heating above 55° to 65° C. It possesses a cytophile group 
which unites with the cell, and completnentophile groups which unite 
with the complements. It may be represented by an arrow, the head 
being the haptophore group and the tail lines the various comple- 
mentophile groups (Fig. 30). 

The function of the amboceptor is, therefore, to fasten the active 
complement to the cell. 

Fig. 30. 



aiC>HH}<s 



A B 

Amboceptor. 

Agglutinins. When foreign cells or bacteria are injected into 
suitable animals their sera develop the property of agglutinating in 
vitro the particular cells or bacterium used in the injection. This 
action resides in an albuminous element of the serum, consisting of 
the free receptors of Order II. thrown off from the cells chiefly 
affected by the injections. These receptors differ from those con- 
stituting the hemolytic amboceptor. They are thermostabile. They 
possess a haptophore group uniting with the cell or bacterium and 
an agglutinophore or zymophore group which brings about this 
agglutination. The agglutinophore group may be destroyed while 
the haptophore group persists (agglutinoids). No complement is 
necessary for their action (Fig. 28). 

The nature of the agglutinating process is very obscure. 

Precipitins, Coagulins. When defibrinated blood or any albumin 
in solution is injected into suitable animals their sera develop the 
capacity of precipitating in vitro the albumins used in the injections. 
The reaction is highly specific (cf . Serum Blood Test). The same laws 
which govern the agglutinins apply to the precipitins. 

Antitoxins, Antiagglutinins, Anticomplements, Antiamboceptors, 
Anticytolysins. The injection into suitable animals of toxins, agglu- 
tinins, complements, amboceptors, or cytolysins gives origin to bodies 
in the serum which annul in vitro the properties of the principles 
injected. These bodies are receptors of Order I. 

The antitoxins are free receptors which unite with the haptophore 
group of the toxins and prevent the union of the toxin with the 
susceptible cell. Antiagglutinins and anticomplements are devel- 
oped in the same manner. 

The injection of heated cytolytic serum, free from complement, 
produces an antiamboceptor which unites with the cytophile group 

10 



] 46 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 

of the amboceptor, thus preventing its union with the susceptible 
cell, but leaving the complementophile group still capable of attract- 
ing the complement. 

The injection of a bactericidal or cytolytic serum containing both 
amboceptor and complement, produces both antiamboceptor and 
anticomplement (Fig. 29). 

Clinical Types of Leucocytosis. 

Digestion Leucocytosis. Although digestion leucocytosis was 
one of the earliest of observed phenomena regarding leucocytes 
(Nasse, Virchow), owing to the uncertain methods employed by some 
later observers, and to the subsequent discovery of other marked 
physiological variations in the numbers of the cells, the occurrence 
of a leucocytosis referable to digestion was not fully accepted until 
Pohl, in dogs, and Limbeck and R. MUller, and Rieder, in man, 
investigated the subject with the necessary precautions against pos- 
sible disturbing factors. 

It is now evident that in order to demonstrate digestion leucocy- 
tosis it is necessary to know the normal percentage of each individual, 
and not to rely upon general averages, as the effect of digestion is 
not great, and the leucocytes at periods well distant from meals vary 
considerably according to the health, age, state of circulation, nutri- 
tion, and digestion, of the individual. With these precautions it 
has been found that a full meal raises the number of leucocytes in 
the average healthy subject about 33 per cent. (Rieder), beginning 
certainly within one hour, reaching a maximum in three to four 
hours, and thereafter gradually declining. The exact figure reached 
cannot have much significance, for the reasons above stated, but in 
adults the maximum is not often above 15,000 to 16,000. In healthy 
fasting subjects the increase is rarely over 3000 cells, but in invalids 
the variations are slightly greater. 

A failure of digestion leucocytosis in healthy adults is sometimes 
observed and may be referred to a prolongation of the process, or to 
chronic torpidity of the intestines, or to accidental causes. 

The quality of the food has sometimes a distinct effect on the 
grade of leucocytosis. Highly albuminous meats, readily digested 
and absorbed in considerable quantity, have much more influence 
upon leucocytes than a meal of vegetables and fats. Indeed, although 
Duperie has reported digestion leucocytosis after exclusively vege- 
table diet, it is usually not seen in any vegetarian animal, probably 
because of slower digestion and absorption. 

Of the disorders in which digestion leucocytosis may be expected 
to fail the mildest are those marked by torpidity of stomach and 
bowels, which lengthens the time and diminishes the completeness 
of digestion and absorption (Rieder). R. Miiller found it difficult 
to excite leucocytosis in anemic subjects, except by very large meals, 
until the general condition of the patient was much improved, and 
Rieder also observed no increase but even a diminution of white cells 
in similar cases. Among various hospital cases confined to bed from 



THE LEUCOCYTES AXB LEUCOCYTOSIS. 147 

chronic complaints the lencocytosis sometimes exceeded the normal 
limits, sometimes was absent. 

When from any other cause the leucocytes are distinctly increased, 
as in pregnancy, inflammatory disease, etc., digestion usually fails to 
produce a further demonstrable increase. 

In children^ up to fifteen years of age, most observers have found 
more marked digestion lencocytosis than in adults, especially after a 
meat diet (v. Jaksch, Rieder). The first digestive activity in the 
newborn infant excites a considerable lencocytosis, Schiff finding 
an increase from 19,000 to 27,000 one hour after the first nursing, 
and 36,000 at the end of forty-eight hours, after several nursings. 
Between the tenth and fifteenth years Rieder found leucocytoses of 
3000 to 9000, the average increase being greater than in adults. In 
the aged it is somewhat less than in adults (Pohl). 

In carcinoma of the stomach, R. Miiller first called attention to the 
absence of distinct digestion lencocytosis which marks this condition, 
finding that without regard to the presence of HCl or pepsin these 
cases do not show a pronounced increase of leucocytes after meals. 
From later reports it appears that about 90 per cent, of cases of gas- 
tric cancer fail to show any distinct digestion lencocytosis (2000 to 
3000), although there are some clear exceptions to the rule, and more 
examples of a slight increase. This failure of lencocytosis is appar- 
ently independent of the presence of HCl or pepsin, occurs when 
stenosis does not exist, and is referred by Schneyer to involvement 
of the neighboring lymphatics, and to complicating gastric catarrh. 
In very advanced cases it is perhaps invariably absent (Hartung). 
In various other conditions sometimes simulating gastric cancer, as 
benign stenosis, ulcer of stomach, chronic gastric catarrh (Schneyer, 
Capps, Cabot), as well as in carcinoma of other viscera (Hartung), 
well-marked digestion lencocytosis is the rule. 

As a diagnostic test, the absence of digestion lencocytosis has not 
been found to give as reliable evidence as was first hoped, because, 
as recently shown by Sailer and others, it is too frequently absent 
in other conditions. As evidence against cancer, the presence of 
digestion lencocytosis is, however, of considerably greater value, 
though by no means positive. Nevertheless the examination of the 
blood deserves a place in the diagnosis of this often obscure disease. 

Origin of Digestion Leucocytosis. The essential factor in digestion 
leacocytosis is, without doubt, the absorption of a considerable quan- 
tity of albuminous principles. This absorptive process has been 
shown by Hoffmeister to excite a considerable proliferation of mono- 
nuclear cells in the adenoid tissue throughout the gastro-intestinal 
tract. It would seem that such increase of mononuclear cells must 
necessarily cause an increased number of these cells to reach the cir- 
culation, and Pohl, in fact, reported finding the mesenteric veins 
during digestion in dogs, much richer in leucocytes, both mononu- 
clear and polynuclear, than the arteries. Rieder, however, could not 
find such a disproportion between veins and arteries, and in the 
absence of other experimental data it becomes necessary to suppose 
that the marked increase of lymphocytes which characterizes digestion 



148 GENERAL PHYSIOLOGY AND PATHOLOGY. 

leucocytosis is referable to an increased outpour of lymph from the 
thoracic duct, the occurrence of which during digestion there are 
obvious reasons for accepting. 

Since the proportions of mononuclear and polynuclear cells are not 
greatly disturbed in digestion leucocytosis, the marrow must furnish 
a considerable number of neutrophile leucocytes, and the chemotactic 
properties of the absorbed albumins must be regarded as the chief 
cause of their outpour. 

Regarding the exact proportions of different cells in digestion 
leucocytosis data are not numerous but sufficient to show that this 
is a ^' mixed leucocytosis/' both lymphocytes and polynuclear cells 
being increased, more especially the lymphocytes. The eosinophiles 
are usually reduced (Rieder). 

Leucocytosis after Muscular Exertion and from Perspiration. In each of four 
contestants in a twenty-five mile running race, Larrabee found leucocytosis, 
14,400 to 22,200 cells, and a few myelocytes. The subjects lost, during the 
race, from two and a half to five and a quarter pounds in weight, and were 
greatly exhausted. This leucocytosis is probably of similar significance with 
that observed after convulsions. 

In twenty-nine children subject to spontaneous sweats, or made to sweat by 
hot-air baths, Hannes found leucocytosis in 77 per cent. In seven cases there 
was an increase of 3000 cells ; in 15, an increase of 3000 to 5000. The leuco- 
cytosis disappeared within one-half hour. 

Leucocytosis of Pregnancy. The occurrence of moderate leuco- 
cytosis in the latter months of pregnancy, though previously known, 
was first fully studied by Halla, who found a marked increase in ten, 
a slight increase in six (12,000 to 13,000), and no change in three, 
out of nineteen cases examined. 

Rieder eliminated any possible effects of digestion, allowing his 
patients to fast sixteen hours, and found a leucocytosis, averaging 
13,000 cells, in only twenty-one of thirty-one cases, all the excep- 
tions being multiparae. Of seventeen multiparae leucocytosis was 
absent in ten. Limbeck found 11,000 to 13,000 cells in each of four 
cases examined, and Cabot reports unusually high counts (25,000 to 
37,000) in three, and the ordinary increase in nine cases. Hubbard 
and White report polynuclear leucocytosis in 80 per cent, of their 
fifty-five cases, most marked and constant in young primiparse. The 
averages twenty-four hours before labor were : primiparse 15,000, 
multiparas 11,700. Before the end of the third month no leucocy- 
tosis is to be expected (Rieder), but the exact period of its appear- 
ance has not been determined. Rieder made the interesting obser- 
vation in six cases that in the ninth month of first or subsequent 
pregnancies, whether leucocytosis exists or not, digestion causes a 
diminution instead of an increase of white cells. 

After 'parturition^ the leucocytes gradually diminish, reaching the 
normal usually in four to fourteen days, but this diminution is fre- 
quently interrupted by slight disturbances referable to the repair of 
marked erosions or tears of the genital tract, to mild disorders of the 
breasts, and to the loss of blood. During and immediately after 
childbirth a considerable increase of leucocytes has been observed in 



THE LEUCOCYTES AND LEUCOCYTOSIS. 149 

a moderate number of reported cases (Kosina and Eckert^ Malas- 
sez, Fouassier^ Eieder). 

The studies of Zangemeister and Wagner have important bearing 
on previous work in this field. They found that among healthy 
women between twenty-one and thirty-four years of age the leuco- 
cytes varied greatly, and in sixteen there were over 12,500 white 
cells. In fifty-seven pregnant women about the same figures and 
variations were obtained, except that counts below 10,000 disap- 
peared, and twenty-one gave over 12,500. Parturition increased 
the leucocytes in all of sixty-three cases up to the birth of the child, 
when the count promptly fell. In childbed, seventy-five cases, there 
was usually a steady decrease, sometimes interrupted by after-pains, 
absorption of lochia, etc. 

The leucocytosis of pregnancy has been referred to various causes, 
none of which seem to meet all the requirements. Virchow found 
a parallel between the increase of leucocytes and the widening of 
the uterine and abdominal lymphatic vessels and nodes and the in- 
crease of metabolism in the uterus and its contents. Mochnatscheff^s 
comparisons of the numbers of leucocytes in the finger blood and in 
the cervix uteri do not seem calculated to demonstrate an increased 
supply of any variety of cell from the latter region. Limbeck sug- 
gests that the changes in the breasts are the chief factor, recalling 
the round-cell infiltration which many such glands show, as an indi- 
cation of very active cellular processes. He, with others, has 
supposed that this leucocytosis, like that of the newborn, may 
represent a continuous effect of digestion, an opinion which cannot 
be accepted, since digestion leucocytosis is usually suppressed in late 
pregnancy. Considering the behavior of leucocytes in general, it 
seems hardly a matter of surprise that the active cellular processes 
in the breasts, uterus, vascular system, and fetus, and the associated 
increase of metabolism should, when instituted for the first time, 
find a sympathetic excitement in the blood-producing organs. Being 
a " mixed leucocytosis,'^ with all but eosinophiles normally repre- 
sented, this leucocytosis is probably not either inflammatory or toxic. 

The Leucocytosis of the Newborn. That the blood of new- 
boru infants invariably shows a well-marked leucocytosis was noted 
by many early observers, in greatest detail by Hay em, who found 
an average at birth of 16,000 to 18,000, a rapid decrease to 7000 
toward the third to fourth days, when the initial loss of weight 
becomes most marked, and a subsequent increase to 9000 or 11,000, 
with beginning increase in body weight. In children at eight 
months he found 14,000 to 21,000 white cells, while by the fifteenth 
month the numbers commonly dropped to 10,000, and he noted also 
that the increase was largely in the nature of a lymphocytosis, the 
small lymphocytes being four to five times as numerous as in adults. 

These main features of the leucocytosis of the newborn appear 
again in Rieder's observations, who found slightly greater numbers, 
14,200 to 27,400, in a few subjects, in whom the initial decrease on 
the third to fifth days was also well marked and apparently unaffected 
by the first demands on digestion. Rieder found the leucocytosis of 



150 GENERAL PHYSIOLOGY AND PATHOLOGY. 

the child uniformly greater than that of the mother^ and, except for 
the preliminary decrease of the first week, much more persistent. 
His differential counts show that the lymphocytes are not in exces- 
sive proportion at birth, but that this excess becomes established 
later. (So also Gundobin.) His cases showed at birth a considerable 
excess, also, of eosinophile cells. 

Schiff examined eleven infants twice daily for two weeks, his 
results showing excessive variations in the numbers of leucocytes in 
the first few days (10,000 to 36,000), referable apparently to over- 
feeding and diarrhea. The preliminary decrease beginning on the 
third to fifth days is quite noticeable in his tables. At the end of 
two weeks the leucocytes numbered 10,000 to 15,000. 

Gundobin's observations show that the leucocytes remain high 
during the first year of infancy (11,000 to 14,000) ; that the excess 
of lymphocytes is established before the tenth day and persists 
throughout the first two years (50 to 65 per cent), when they begin 
to decline, reaching the proportions of the adult about the eighth to 
tenth years. 

Observations on the Leucocytosis of the Newborn. 

Hayem average for forty-eight hours, 18,000 

" third to fourth day, 7,000 

after fifth day, 9,000 to 11,000 

Otto ten to twenty-five hours, 23,000 to 25,000 

Schiff forty-eight hours 10,000 to 32,800 

" fourth to eighteenth day, 12,000 to 13,000 

Woino-Oransky . . . at birth, 16,980 

fourteen hours, 20,980 

" second day, 31,680 

Gundobin last day, fetus, 8,053 

at birth, 19,600 

" twenty-four hours, 23,000 

" forty-eight hours, 17,500 

Kruger one to three days, 18,000 

after third day, 15,000 

Rieder at birth, 14,200 to 27,400 

second to fourth day 8,700 to 12,400 

after fourth day, 12,400 to 14,800 

From the above conflicting reports it is difficult to give precise 
details regarding the leucocytosis of the newborn. Rieder's obser- 
vations seem to the writer the most reliable, in which a moderately 
high proportion of white cells is found at birth, a distinct decrease 
on the second to fourth days with the diminution of weight, followed 
by a less marked but persistent leucocytosis. Further very careful 
studies are needed in this field. 

Regarding the origin of this form of leucocytosis, opinions are at 
variance. That the initial increase is referable to concentration of 
the blood and venous stasis seems to be true both of red and of white 
cells. The preliminary decrease the writer believes to be due to 
improvement in the venous circulation with relief of cyanosis, and 
the absorption of fluids. The subsequent increase and permanent 
leucocytosis of infancy, being largely a lymphocytosis, probably repre- 
sents to a considerable extent continuous digestion leucocytosis. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 151 

That it is not entirely referable to digestion is indicated by the low 
counts found by Rieder on the second to fourth days, after frequent 
nursing. 

Post-hemorrhagic Leucocytosis. A well-marked leucocytosis 
following acute hemorrhage was described by the older writers 
(Virchow, Xasse, etc.), but the detailed study of this condition was 
reserved until Lyon and Huhnerfauth investigated the effects of 
hemorrhage by the newer methods. 

Huhnerfauth found in nine dogs, losing about 4 per cent, of their 
body weight by acute hemorrhage, that the leucocytes were often 
slightly diminished immediately after the operation, much increased 
(maximum 45,000) on the following day, and that this increase per- 
sisted in some degree for two to three weeks. Lyon, in similar 
experiuients, also found an initial decrease a few minutes after the 
hemorrhage, but soon a very marked increase of the white cells, 
reaching its highest point (62,000) within six to eight hours, declin- 
ing rather rapidly after three to four days, but persisting thereafter 
in moderate degree for days or weeks. In the human subject after 
a surgical operation attended with dangerous hemorrhage, Lyon 
found, after one hour, 41,625 leucocytes ; after five days, 14,300, fol- 
lowed by a slight increase for one week. In a case of leukemia, 
splenectomy caused the leucocytes to jump from 463,000 to 850,000 
several hours before death from hemorrhage and shock. Rieder 
repeated the experiments on dogs, finding the usual changes, as a rule, 
but in one instance a large hemorrhage failed to cause leucocytosis. 
In differential counts he observed that most of the leucocytes were 
polynuclear, finding as high as 97 per cent, of neutrophile cells 
immediately after the hemorrhage. In the human subject he was 
unable to find very pure examples of post-hemorrhagic leucocytosis, 
but reported 15,000 cells after pulmonary hemorrhage in phthisis ; 
32,600 (1,300,00() red) after hemorrhage from cancer of the uterus ; 
26,500 (1,985,000 red) in ulcer of stomach. 

Head demonstrated a slight temporary diminution of leucocytes 
occurring a few minutes after severe hemorrhage in dogs, which was 
soon replaced by leucocytosis lasting seven days. 

The neutrophile cells are usually the ones most affected, the eosin- 
ophiles sometimes appearing in considerable numbers (Lyon, Hall 
and Eubank), and the small lymphocytes showing a relative increase 
(Rieder). Ehrlich and Lazarus found 13.7 per cent, of myelocytes 
in a marked post-hemorrhagic leucocytosis, and in one of the writer's 
cases of splenectomy with profuse hemorrhage the blood for some 
days closely resembled that of myelogenous leukemia. 

In general, the leucoci/tosis following hemorrhage is in proportion to 
the extent and rapidity of the loss of blood, but it usually disappears or 
greatly diminishes long before the red cells are restored. The infusion 
of fluids has been found to considerably increase the leucocytosis. 
This result has been repeatedly observed in cases of splenectomy 
(q. v.). 

The not infrequent failure of post-hemorrhagic leucocytosis, as 
reported by Rieder, Stengel, Cabot, and others, has not been ex- 



152 GENERAL PHYSIOLOGY AND PATHOLOGY. 

plained. In such cases the remaining cells may be largely lympho- 
cytes (Stengel). Erb^ however, reported marked absolute lympho- 
cytosis after hemorrhage. 

It is generally agreed that the chief factor in the production of 
post-hemorrhagic leucocytosis is the outpour of lymph which restores 
the lost bulk of blood. Were this the only factor, however, the new 
cells ought to be principally lymphocytes, and the high proportion 
of neutrophile cells commonly seen points to a special draining of the 
marrow or possibly to increased cellular activity in this tissue. 
Against this view are the facts that normoblasts are not numerously 
present until the second to the third day, while the leucocytes are 
most numerous after a few hours. 

The old opinion of Samuel, Virchow, and others, that the more 
cohesive neutrophile cells are retained in the vessels is perhaps still 
worthy of consideration. After the infusion of salt solution the high 
percentage of polynuclear cells can be partly referred to the chemo- 
tactic influence of this fluid upon the marrow. 

Cachectic Leucocytosis. Of the varieties of leucocytosis classi- 
fied by Rieder that which is frequently associated with severe anemia 
and cachexia is the least homogeneous. In its causation figure 
many of the conditions already shown to frequently excite leucocy- 
tosis, especially loss of blood and inflammatory processes. Yet there 
exists a considerable group of cases, marked by continuous leucocy- 
tosis, in which other influences combine to increase the production of 
white cells, and to develop a somewhat peculiar form of leucocytosis 
which deserves a special description. 

White, Cruveilhier, Paget, and others before them, who first 
described cachectic leucocytosis, regarded the excess of cells as frag- 
ments of the neoplasm. Andral and Gavaret, Chaillou, and Vidal, 
recognized these cells as leucocytes. This correct interpretation was 
soon followed by the more detailed study of the condition by Lucke, 
Sappey, Nepveu, and especially by Hayem, Alexander, Schneider, 
Pee, Reinbach, and Rieder, each of whom have contributed largely 
to the present knowledge. 

Some of the clearest examples of this sort of leucocytosis are seen 
in the cachexia of malignant tumors, where the combination of 
hydremia, local inflammatory processes, and specific toxemia are the 
principal factors concerned. 

Chronic anemia may lead to increase of leucocytes in the circula- 
tion through the watery condition of the blood, the increased activity 
of red marrow, here often moderately hyperplastic, and the lowered 
blood pressure. Illustrations of the working of these influences are 
seen in the increase of post-hemorrhagic leucocytosis after infusion, 
and in the periodical appearance of normoblasts and mixed leucocy- 
tosis in advanced chlorotic anemia. Yet chronic hyperemia and 
extreme hyperplasia of the red marrow alone are not necessarily 
accompanied by leucocytosis, but often exist with diminished leuco- 
cytes, as is usually seen in uncomplicated primary pernicious anemia, 
so that it is impossible to ascribe to chronic hydremia more than a 
predisposing influence in cachectic leucocytosis. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 153 

Horbaczewski and Lowit^ ascribe both the hydremia and the leuco- 
cytosis of cachexia to the lymphogogic and chemotactic influence of 
nucleins, which in increased quantity are set free by the excessive 
destruction of tissue elements^ but Lowit claims from his experi- 
mental study of the subject that increased floiv of lymph alone is incap- 
able of "producing leucocytosis. 

Local inflammations are probably the most frequent causes of 
marked cachectic leucocytosis. These may be traced in the growing 
edges or ulcerating surfaces of malignant tumors, in various internal 
suppurative or necrotic processes in syphilis and tuberculosis, and 
in exacerbations of underlying chronic inflammations. 

The special involvement of the blood-forming organs by neoplasms 
and inflammations has been found not only to increase the leuco- 
cytes in the circulation, but at times to give a special character to the 
leucocytosis which may be of diagnostic service — e. g., eosinophilia 
and lymphocytosis with sarcoma of bone or lymph nodes. While 
sarcoma is usually attended with lymphocytosis, carcinoma, on the 
other hand, usually excites a polynuclear leucocytosis, a difference 
which may perhaps be referred to the freedom of the lymph paths 
in the former and their occlusion in the latter case. 

Finally, there is to be considered as the essential element in 
cachectic leucocytosis a chronic toxemia^ which, in several conditions, 
is of more or less specific character. 

Some importance here attaches to the observations of Hayem, who 
noted the disappearance of persistent leucocytosis (10,000 to 21,000) 
in four cases after removal of cancers of the breast, while a recur- 
rence of the tumor he claims to have predicted from a slight per- 
sistent increase of leucocytes. Grawitz has shown that injections of 
extract of carcinomatous tissue and of tuberculin have a marked 
lymphogogic effect. The distinct cachexia which often foreshadows 
the appearance of a malignant neoplasm is abundant clinical evidence 
that these new-growths elaborate powerful toxins, but it has never 
been conculsively shown that these toxins have any particular influ- 
ence upon leucocytosis, which in the majority of cases seems to arise 
from other factors. The same conclusion must be drawn from the 
absence of any uniform relation between cachectic leucocytosis and 
the extent of miliary tubercles and gummata, or the extent, location, 
and histological structure of malignant tumors. General miliary 
tuberculosis, acute or chronic, usually fails to excite leucocytosis. 
The writer has seen severe anemia without leucocytosis, with extensive 
gummata in liver, spleen, and thoracic and abdominal lymph nodes, 
and in general carcinomatosis. 

Indeed, in a review of many reported cases and in the writer's own 
experience, in the great majority of cases of tertiary syphilis, tuberculo- 
sis, nephritis, in a large proportion of carcinomata, and in a rather 
smaller proportion of sarcomata, cachexia is unaccompanied by leuco- 
cytosis unless there is distinct local inflammation, necrosis, or hemor- 
rhage. Whence it may be stated as a general rule that marl-ed 
leucocytosis in the course of cachexia suggests a search for one of these 
complications. 



154 GENERAL PHYSIOLOGY AND PATHOLOGY. 

Antemortem Leucocytosis. In 1883 Litten reported from 
several handed examinations of the blood of forty moribund cases in 
whom no leucocytosis had previously existed, that he had found in 
many a more or less pronounced increase of white cells, beginning at 
a variable period before death. 

When dissolution was rapid no leucocytosis was found, but when 
prolonged, the increase of white cells was very marked (one to five 
of red). Litten was unable to offer a plausible explanation of the 
phenomenon and failed to give exact numerical estimates and impor- 
tant clinical details of his cases, so that his interesting observations 
attracted but little notice. 

In 1886, Gottlieb found 30,000 leucocytes six hours before death 
in a case of pernicious anemia which had previously shown no 
increase. Rieder found well-marked antemortem leucocytosis in 
three of four cases, in one of which 89.5 per cent, of 60,000 cells 
were polynuclear. The case not showing leucocytosis was compli- 
cated with aspiration pneumonia. Many later reports of isolated 
observations on this variety of leucocytosis have proven the frequency 
of its occurrence, but have not added greatly to the knowledge of 
its special peculiarities or its significance. 

It appears most probable that a considerable variety of factors is 
concerned in the antemortem increase of leucocytes. Cohnheim^s 
theory that diminishing blood pressure causes an increased outpour 
of lymph is supported by the occurrence of post-hemorrhagic leuco- 
cytosis, but not by the high percentage of polynuclear cells and of 
nucleated red cells usually present. Litten's suggestion that there 
is an unequal distribution of leucocytes in favor of the peripheral 
capillaries is in accord with the known effects of stasis. Limbeck's 
opinion that antemortem leucocytosis probably results in most cases 
from terminal infections may certainly apply to many instances 
marked by excess of polynuclear cells, but not to all, especially to 
those rare cases showing lymphocytosis. 

The character of antemortem leucocytosis seems to depend largely 
upon the precedent condition. In leukemia and inflammatory dis- 
eases the cells principally increased are the polynuclear forms of the 
marrow, and along with these many nucleated red cells and some 
myelocytes are commonly drawn into the circulation. In the ter- 
minal stages of lymphatic leukemia the lymphocytes may be greatly 
increased. 

Pronounced antemortem lymphocytosis has been seen in perni- 
cious anemia by Cabot and by the writer, in diphtheria and other 
conditions in children, in typhoid fever, and to a less extent in 
malaria. Its rather frequent occurrence is constantly leading to 
erroneous diagnoses of acute lymphatic leukemia. 

It would seem that the effects of terminal inflammations, ante- 
mortem dissemination of intestinal and other bacteria, antemortem 
hyperpyrexia, vasomotor paresis, serous exudates, diarrhea, lack of 
fluids ordinarily ingested, etc., have not received sufiicient attention 
in this important field, and that the entire subject needs investigation 
on a much more elaborate scale than has yet been attempted. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 155 

Experimental Leucocytosis. 1. By Drugs and Chemicals. The 
earliest observations on experimental leucocytosis were those of Hirt, 
who, in 1856, reported an increase (100 to 300 per cent.) of white 
cells following the administration of tr. ferri pom., tr. myrrh., etc. 
The same effect was noted by Meyer from turpentine, camphor, and 
oil of peppermint. Later Pohl, in the endeavor to explain the origin 
of digestion leucocytosis, tested the effects of a large number of drugs, 
finding that the aromatic extracts and oils, vegetable bitters, certain 
alkaloids (piperin, strychnine, and others) caused a rather distinct 
(40 to 120 per cent.) leucocytosis, when administered to fasting dogs. 
Alcohols, salts of various alkalies, lead acetate, cupric sulphate, calo- 
mel, caffeine, and quinine he found to be inert, and oxide of iron 
usually so. In general these leucocytoses appeared within one-half 
hour and disappeared in two hours, and were therefore less marked 
and persistent than those excited by the absorption of digested albu- 
mins. 

Repeating these experiments on man, Binz and Limbeck induced 
leucocytosis by means of camphor and oils of cinnamon, peppermint, 
and anise, but Rieder found it impossible to secure much effect from 
extract of gentian or tincture of myrrh. Even such a bland fluid as 
solution of common salt in subcutaneous injection has been shown 
to excite transitory leucocytosis (Lowit, Rieder). 

Bernard, and Meyer and Seegen found the leucocytes doubled after 
the administration of 20 gt. of ether. 

Horbaczewski^ found a moderate diminution of leucocytes in man 
after administraion of quinine and of atropine, and a considerable 
increase from antipyrin, antifebrin, and pilocarpine. The writer 
has failed entirely to produce distinct leucocytosis in rabbits by use 
of pilocarpine. Gazza reports that digitalis in therapeutic doses causes 
leucocytosis ^\ hich increases until death if the drug is pushed to fatal 
doses. 

Winternitz studied the effects of a great variety of drugs, with 
special reference to the relation between the grade of local inflamma- 
tion and the degree of intravascular leucocytosis. He divided these 
agents into two classes, one of which, including salts and simple 
irritants such as free acids and alkalies, by subcutaneous injection, 
induced slight local disturbance and moderate leucocytosis and fever ; 
while the other, including vesicants, sapotoxin, digitoxin, silver 
nitrate, copper sulphate, mercurials, and antimonials, produced 
aseptic suppuration and higher leucocytosis. He, therefore, estab- 
lished for these agents the same relation between local reaction and 
general leucocytosis that Limbeck has shown for bacterial cultures. 

Moderate grades of leucocytosis have been reported by Wilkinson 
from the administration of potassium iodide, quinine, salicin, etc., 
from nuclei n by v. Jaksch, from salicylic acid by Schreiber and 
Zandy, from morphine and sodium salicylate by Bohland. The 
writer once counted 28,000 cells, mostly polynuclear, in coma from 
morphine, forty-eight hours before death. All of these observations 
point to the necessity of considering the effects of drugs in the clin- 
ical study of leucocytosis in disease. 



156 GENERAL PHYSIOLOGY ASD PATHOLOGY. 

2. By Bacterial Cultures. Limbeck injected cultures of bacteria 
into the knee-joints of fasting dogs, and found the maximum leuco- 
cytosis at the end of six to twenty-four hours, two to three times the 
normal numbers being commonly reached, and 88 to 93 per cent, 
of the cells being polynuclear. The pyogenic staphylococci were 
most active, increasing the leucocytes sixfold to sevenfold ; strepto- 
coccus pyogenes came next, and Friedlander^s pneumobacillus third, in 
effectiveness. 

Rieder repeated these experiments, using cultures from solid media 
only. He showed that such material was very much less active in 
producing leucocytosis than are the fluid cultures, that the increase 
is preceded by a transient decrease of cells, and that the injections 
may be followed by persistent hypoleucocytosis and death of the 
animal. 

A sufficient number of observations have since shown that prac- 
tically all pathogenic bacteria in subcutaneous or intravenous injec- 
tion exert positive chemotactic influence upon leucocytes. The 
duration of the period of diminution and the degree of subsequent 
increase of leucocytes vary considerably with the different species, 
cultures, and individuals. 

8. By Bacterial Proteins, etc. After Limbeck^s demonstration of 
the chemotactic effects of bacterial cultures, it was soon shown that 
various bacterial and other extracts are equally powerful excitants of 
leucocytosis, as cadavarin, putrescin, ptomaines of decomposing 
flesh, extracts of sterilized cultures of staphylococci, and phlogosin, 
a crystalline alkaloid obtained from similar cultures (Scheurlen, 
Grawitz,^ Behring,^ Arloing, Leber^). 

The more complete separation of the active chemotactic principles 
of bacterial cultures was accomplished by Buchner follow^ing Xencki's 
method. Buchner found that the leucocytes are influenced solely by 
the albuminous principles of bacterial cultures, and these he isolated 
from a considerable number of species, in the form of bacterial 
^' proteins." From bacillus pyocyaneus he secured a protein which, 
after four daily doses of two grammes, increased the leucocytes seven- 
fold. Testing the effects of the decomposition-products of animal 
tissue, peptone, alakli-albumin, and calcium, he found these agents 
comparatively inactive and concluded that the principles derived 
from inflamed tissue are unimportant adjuncts to the bacterial pro- 
teins in exciting inflammatory leucocytosis. 

Koch's tuberculin was early shown to cause at the height of the 
reaction a moderate and rather transitory increase of polynuclear leu- 
cocytes and a simultaneous diminution of eosinophile cells (Uskow, 
Tschistovitch, Zappert). Botkin found it impossible to increase the 
effects by repeated daily doses. A marked and persistent increase 
of eosinophile cells, reaching in one case 85 per cent, and in another 
continuing for ten weeks, following the febrile reaction and frequently 
associated with cutaneous eruptions, has been noted by Grawitz,^ 
Neusser,^ Canon, Botkin,^ and Zappert. 

A recent extensive study by Liebmann indicates that tubercu- 
lin influences both leucocytes and the tubercle bacillus, drawing 



THE LEUCOCYTES AND LEUCOCYTOSIS. 157 

each into the circulation, in man and lower animals. Liebmann 
could lind no great uniformity in the behavior of eosinophile cells, 
but in rabbits and guinea-pigs tuberculin caused a marked increase 
of neutrophile cells, a moderate increase of mononuclear leucocytes, 
and the appearance of a moderate number of mast-cells. 

That leucocytosis follows the injection of a great variety of bacte- 
rial filtrates and extracts has been shown also by a large number of 
later experiments. The grade of leucocytosis varies considerably, 
depending on the quantity and virulence of the toxin and the sus- 
ceptibility of the animal. 

Rieder found the leucocytes increased twelvefold after three daily 
injections of pyocyanin. Occasionally one encounters persistent 
hypoleucocytosis, as did Romer after using large injections. 

4. By Various Organic Principles. The Dorpat school first studied 
the effect upon leucocytes of another group of agents, including 
several aniuial principles. They found hypoleucocytosis followed by 
hyperleucocytosis in marked degree after the injection of fibrin fer- 
ment, pepsin, peptone, hemoglobin, decomposing albuminous fluids, 
pus, and crushed lymphoid tissue (Hirt, Bojanus, Hoffman, Him- 
melstjerna, Heyl, Grotli). 

Lowit studied the effects of various albuminous and organic prin- 
ciples, injected into animals, finding hypoleucocytosis followed by 
varying grades of hyperleucocytosis from hemialbumose, peptone, 
pepsin, nucleinic acid, nuclein, urea, sodium urate, curare, and pyo- 
cyanin, and tuberculin. 

Vegetable albumins were first used to excite local purulent 
exudates by Buchner, who obtained aseptic pus in large quantities 
by the injection into the pleura of ground wheat, pus, fossil earth, 
and gluten casein. Rieder and Halm also secured a high grade of 
leucocytosis by the same agents. 

Goldscheider and Jacob proceeded still further in the study of the 
chemotactic properties of animal extracts, finding powerful effects 
from the injection of glycerin extracts of spleen, thymus, and mar- 
row, but none from extracts of thyroid, liver, kidney, and pancreas. 

Applications of Experimental Leucocytosis. In 1894 Pawlowsky 
reported that he had saved animals from fatal doses of anthrax by 
injections of papayotin, abrin, and ricin, which are very active exci- 
tants of leucocytosis, and he recommended that anthrax in man be 
treated by local injection of these agents. In guinea-pigs and rabbits 
in which leucocytosis had been excited by papayotin, or better by 
abrin, injections of tubercle bacilli were less frequently followed by 
generalization of the tuberculous process, sometimes by greater ten- 
dency to fibrous growth in the tubercles, or even by total disappear- 
ance of tubercles already existing. 

In 1895 Lowy and Richter reported that rabbits in which they 
had established marked leucocytosis by repeated injections of " sper- 
min '' withstood injections of pneumococcus cultures three to four 
times as large as were required to kill control animals. The thera- 
peutic effect was much less marked when the bacterial injections 
followed those of spermin within twenty-four hours or less. 



158 GEXEEAL PHYSIOLOG Y AXD PATHOLOGY. 

Goldscheider and Mliller then took occasion to recall some unsuc- 
cessful experiments of their own performed on guinea-pigs, in which 
leucocytosis had been excited by injections of splenic pulp extract. 
This procedure they had found to yield no therapeutic influence on 
infections by bacillus diphtherue, tetani, proteus, or pneumococcus. 

Goldscheider and Jacob had also previously attempted, without 
success, to favorably influence by artificial leucocytosis the course of 
typhoid fever and puerperal sepsis. 

In animals which had received injections of albumoses Jacob 
found that subsequent infection with virulent bacterial cultures was 
better withstood if the infection occurred when the leucocytes were 
on the increase from the previous injection of albumose, but when 
the infection occurred in the stage of hypoleucocytosis it was more 
rapidly fatal than in the control animals. Considerable therapeutic 
effect was apparently obtained when the administration of albumose 
occurred during the increase of leucocytes resulting from the bacte- 
rial injection. 

Hahn was able to retard the progress of anthrax infection in rab- 
bits by previously exciting leucocytosis by means of albumoses, but 
wdth a few favorable results were a larger number of failures. He 
W'Cnt on to show that the bactericidal action of blood both in man 
and animals is increased during the stage of hyperleucocytosis. 

From the foregoing studies it is evident that there is a rational 
basis for the employment of artificial leucocytosis in the treatment 
of some infectious processes, since both the phagocytic and bacteri- 
cidal powers of the blood are thereby increased. It has recently 
been shown that the treatment of some infectious diseases by animal 
serum is ineffective, probably because the serum, rich in immune 
body, " amboceptor,'' is deficient in suitable complements, and various 
attempts have been made to supply such complements artificially. 
Yet the results in man are as yet not very favorable, since there is 
no known method of exciting with impunity continuous leucocytosis 
in the human subject, and the search among lower animals for com- 
plements adapted to the human subject has not thus far succeeded. 
The limitation of puerperal septicemia by excitiDg localized abscesses 
by injections of vesicants, the extrusion of inoperable malignant 
tumors by erysipelas, and the treatment of typhoid fever with pyocy- 
anin illustrate some of the practical difficulties in the way of this 
branch of therapeutics. 

BiBLTOGEAPHY. 

Leucocytes. 

Alexander. These de Paris, 1887. 
Almqnist. Virchow's Archiv, Bd. 169, p. 17 
Altmann. Die Element arorganismen. 

Andral Gavaret. Traite de Hematocliniqiie, Paris, 1843. 
Arnold. ' Virchow's Archiv, Bd. 132, p. 502. ' Ibid., Bd. UO, p. 411. ' Ibid. 
Bd. 161, p. 284; Bd. 163, p. 1. 

Arloing. Compt. Rend. Acad. Sci., T. 106, p. 1365. 

Aschoff. Zeit. f. Allg. Phvsiol., Bd. 1 

Arneth. Deut. Arch. f. kl. Med., Bd. 69, p. 343. 

Bail. Berl. klin. Woch., 1897, Xo. 41. 

Behring. ^ Zeit. f. Hvg., 1890, p. 424. ^ Deut. med. Woch., 18S8, p. 653. 



THE LEUCOCYTES AND LEUCOCYTOSIS. I59 

Bcrfiard. Cited by Limbeck. 

Billitigs. N. Y. Med. Record, vol. xlix, p. 577. 

Binz. Archiv f. exper. Path., Bd. 5, p. 109. 

Bohland. Cent. f. inn. Med., Bd. 20, p. 361. 

Bordet. Annal. Institut Pasteur, 1895, p. 398. 

Botkin. Virchow's Archiv, Bd. 137, p. 476; Bd. 141, p. 238; Bd. 145, p. 369. 
- Dent. med. Woch., 1892, p. 321. 

Bouchut, Duhrisaij. Gaz. med. de Paris, 1878, p. 168. 

Buchner. ^ Berl. klin. Woch., 1890, No. 47. ^ Munch, med. Woch., 1894, p. 
469. 3 Arch. f. Hvg., 1890, Bd. 17, p. 112 

Canon. Deut. liied. Woch., 1892, p. 206. 

Cantacuzene. These de Paris, 1894. 

Capps. Boston Med. Surg. Jour., Nov. 4, 1897. 

ChaiUou. These de Paris, 1865, p. 46. 

Cruveilhier. Compend. de Med., T. 2, p. 63. 

Denijs, Havel La CeUule, 1894. 

Duperie. ReAiie- de Med., 1878. 

Ehrlich. ' Archiv f. Phvsiol., 1879, pp. 166, 571. ^ Gesammte Mittheil. Berhn, 
1891. Die Anaemie, Th: I., 1899. 

Einhorn. Diss. Berlin, 1884. 

Engel. Virchow's Archiv, Bd. 135. 

Eiving. N. A\ Med. Jour., 1895, vol. Ixi. p. 257; vol. Ixii. p. 161. 

File. Lo Sperimentale, 1896. 

Flemyning. Archiv f. micr. Anat., 1891, Bd. 37. 

Fodor. Deut. med. Woch., 1886, No. 36. 

Fouassier. These de Paris, 1876. 

Futcher. Johns Hopkins Bull., 1897. 

Gabritscheivsky. ^ Morphologv of the Blood, cited by Botkin. ^ Annal. Institut 
Pasteur, 1890, p. 346. 3Ibid.,^1894. 

Gartner, Romer. Wien. med. Blatt., 1891, No. 42. Wien. Idin. Woch., 1892, 
No. 2. 

Gazza. La Rif Med., 1901. 

Goldscheider, Jacob. Zeit. f. klin. Med., Bd. 25. 

Goldscheider, Midler. Fort. d. Med., 1895, p. 351. 

Gottlieb. Wien. med. Blatt., 1886, No. 17. 

Grohman. Diss. Dorpat., 1884. 

Grancher. Gaz. med. de Paris, 1876, p. 321. 

Graivitz. ^ Deut. med Woch., 1893, p. 468. ^ Virchow's Archiv, Bd. 110, p. 1. 
3 Charite Annal., Bd. 16, p. 291. 

Gruneberg Virchow's Archiv, Bd. 163, p. 303. 

Gulland. Jour, of Physiol., 1896, p. 385. 

Gumprecht. Deut. Archiv klin. Med., Bd. 57. 

Gundobin. Jahrb. f. Kinderheilk., 1893, p. 187. 

Haetaguroff. Inaug. Diss. (Russian), cited by Botkin. 

Hahn. Archiv f. Hvg., Bd. 28, p. 312. 

Halla. Prag. Zeit. 'f.' Heilk., 1883, p. 198. 

Hankin. Cent. f. Pact., 1892, p. 782. Ibid., 1898, p. 692. 

Hannes. Cent. f. inn. Med., 1901, p. 813. 

Hartung. Wien. khn. Woch., 1895, p. 697. 

Haijem. Compt. Rend. Soc. Biol., 1887, p. 270. 

Head. Jour. Amer. Med. Asso., vol. xxxvii. p. 501. 

Heidenhain. Archiv f. micr. Anat., Bd. 43, p. 423. 

Hermann. Archiv f. micr. Anat., Bd. 37. 

Hirschfeld. ' Inaug. Diss., Berlin, 1897. ^ Berl. kl. Woch., 1901, p. 770. ^ Berl. 
kl. Woch., 1901, p. 1019. 

Hesse. ^ Virchow's Archiv, Bd. 167, p. 231. 

Hirt. Mliller's Archiv, 1856, p. 174. 

Hofmeister. Archiv f. exper. Path., Bd. 22, p. 306. 

Horbaczewski. ^ Monatsch. f. Chemie, 1891, xii. p. 221. ^ Sitz. Wien. Acad. 
Wissen., 1891, Bd. C, Abt. III., p. 101. 

Hubbard, White. Jour, of Exper. Med., 1898, p. 639. 

Huhnerfauth. Virchow's Archiv, Bd. 76, p. 310. 

Jacob. Zeit. f. klin. Med., Bd. 30, p. 447. 

V. Jaksch. Cent. f. inn. Med., Bd. 13, p. 81 

Jolly. Arch, de Med. Exper,, 1902, p. 73. 

Kanthack, Hardy. Jour, of Physiol., vol. xvii. p. 91 



160 GEXEEAL PHYSIOL OGY ASD PA THOL OGY. 

Keng. Jour, of Phvsiol., vol. xv. p. 361. 

Kikodse. (Ref.) Cent. f. Path.. 1891. Xo. 3. 

Klein. Volkmann's Yortrage, 1893, Xo. 87. 

Knoll. U. d. Blutkorp. bei wirbells. Thieren, Sitzungsb. kais. Acad. Wien.. 
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Kolisch. Wien. klin. Woch., 1894, p. 797. 

Kosina, Eckert. Cited bv Rieder. 

Kossel. Zeit. f. Hvg., Bd. 16. 

Kruger. Diss. Dorpat, 1886. 

Kurlojj. Abstracted by Eluiich, Die Anaemie. I., p. 56. 

Larrahee. Joiir. of Med. Research, vol. A-ii. p. 76. 

Leber. ^ Fort. d. Med., 1888, p. 460. - Die Entstehimg d Entzundimg, p. 508. 

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Liehman. Yirchow's Archiv Suppl.. Bd. 144, p. 123. 

Limbeck. Zeit. f. Heilk., 1889, p. 392. 

Litten. Berl. klin. Woch., 1883, p. 405. 

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Loewy. Richter. Deut. med. Woch., 1895, p. 240. 

Lubarsch. Fort. d. Med., 1888, Xo. 4. 

Lucke. Das Carcinom, Erlangen, 1867. 

Lyon. Virchow's Ai'chiv. Bd. 84, p. 207. 

Malassez. ^ Gaz. med. de Paris, 1876, p. 297. -Archiv. de Physiol., 1874, p. 32. 

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Moleschott. Wien. med. Woch., 1854, p. 114. 

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Meyer. Schmidt's Jahrb., Bd. 180, p. 121. 

Meyer, Seegen. Cited by Limbeck. 
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Midler. 1 Zeit. f. Heilk., 1890, p. 213. ^ Cent. f. Path., 1896, p. 529. 
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Xissen. Zeit. f. Hvg., 1889, p. 487. 
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Schmidt. Ziegler's Beitrage, 1892, p. 199. 

Schneider. Wien. med. Woch., 1890, Xo. 36. 

Schneyer. Zeit. f. khn. Med., Bd. 27. p. 475. 

Schreiber, Zandy. Deut. Arch. kl. Med., Bd. 62, p. 242 

Schultze. Archiv f. micr. Anat., Bd. 1, p. 1. 

Schulz. Deut. Archiv klin. Med., Bd. 51, p. 234. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 161 

Schur, Loinj. Zeit. f. kl. Med., Bd. 40, p. 412. 

Sherrington. ^ Proc. Royal Soc, 1894, vol. Iv. p. 161. ^ ibid., vol. Iv., 1893. 

Simon. Amer. Jour. Med. Sci., vol. cxvii. p. 139 

Sorensen. Hoffman-Schwalbe's Bericht, 1876, Abt. III. 

Stahl Botan. Zeit., 1884, Nos. 10-12. 

Stengel. 20th Cent. Practice. 

Stokes, Wegefarth. Johns Hopkins Bull., 1897. 

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Thoma, Lyon. Virchow's Archiv, Bd. 87, p. 201. 

Timofjewsky. Cent. f. Path., Bd. 6, p. 108. 

Trauhe. Cited bv Buchner, Arch. f. Hvgiene, 1890. 

Tschistovitch. Berl. klin. Woch., 1891, p. 835. 

Tumas. Deut. Archiv klin. Med., Bd. 41, p. 323. 

Uskow. Cited bv Botkin. 

Van de Velde. La Cellule, X., 1894. 

Vidal. Archiv gen., 1890, p. 333. 

Vaughan. Med. News, Dec. 23, 1893. 

Weiss. Jahrb. f. Kinderheilk., 1893, Bd. 35, p. 146. 

Welcker. Cited by Rieder. 

Werigo. Annal. Institut Pasteur, 1892. 

Wilkinson. Brit. Med. Jour., 1896, vol. ii. p. 836. 

Winternitz. Archiv f. exper. Path., Bd. 35, p. 77. 

Woino-Or^ansky. Cited bv Gundobin. 

TT'o^;f. Berl. kl. Woch., 1901, p. 1290. 

Zangemeister, Wagner. Deut. med. Woch, 1902, p. 549. 

Zappert. Zeit. f. klin. Med., Bd. 23, p. 296. 



THE OCCURRENCE OF EOSINOPHILE CELLS, MAST- 
CELLS, MYELOCYTES, AND LYMPHOCYTES. 

EOSINOPHILIA. 

Physiological Variations. The number of eosinophile cells in 
the blood of healthy aduhs varies, according to Zappert, between 55 
and 784 per cubic millimetre (0.67 to 11 per cent.), but in the majority 
of individuals the limits are between 1 and 4 per cent. Zappert 
regards 50 to 100 per cubic millimetre as a low normal count, 100 
to 200 as intermediate, 200 to 300 as high normal, and over 300 as 
pathological. 

In children a relatively high proportion of eosinophile cells is the 
rule, and the variations in number are slightly greater. The average 
appears to be about 1 to 2 per cent, greater than in adults. 

There are no uniform changes referable to old age, sex, pregnancy, 
menstruation, or digestion. A slight increase after coitus has been 
observed. According to Horder's observations, eosinophilia is a 
racial characteristic of the natives of South China. While 
Europeans in that locality seldom showed more than 5 per cent, of 
these cells, the healthy Chinese gave an average of 15 per cent., in 
anemia and rheumatism 20 per cent., malaria 12 to 37 per cent., 
leprosy 30 to 42 per cent. 

Pathological Variations. From the fact that eosinophile cells 
may be multiplied many times without passing the limits established 
as physiological, it is obvious that none but considerable changes in 
their absolute numbers can have any distinct pathological signifi- 
cance ; yet the observations on eosinophilia have referred quite as 

11 



162 GENERAL PHYSIOL OGY AND PA THOL OGY. 

much to persistently high or low averages within normal limits as 
to distinct increase or decrease, and a certain pathological signifi- 
cance has been shown to go with these lesser variations. 

Diseases of the Blood. In leukemia the presence of large numbers 
of eosinophile cells was first regarded by Ehrlich as the pathogno- 
monic sign of myelogenous leukemia, but it has since been shown 
that eosinophilia may be very marked in other conditions, and that 
the proportion of these cells in leukemia almost invariably lies Avithin 
normal limits (1 to 7 per cent.). Their total numbers, however, are 
very greatly increased, Eieder's highest estimate reaching 29,000 per 
cubic millimetre. In lymphatic leukemia they are commonly absent. 

The presence of eosinophile myelocytes was regarded by Miiller 
and Rieder as pathognomonic of leukemia, but these cells are not 
infrequently found in other conditions. The writer finds that very 
large darkly staining eosinophile granules in mononuclear cells are 
practically limited to leukemic blood, but isolated examples have been 
seen in malaria (Bignami). 

In chlorosis the eosinophiles may be moderately increased, normal, 
or much diminished. Zappert was unable to verify Neusser's belief 
that their absence in chlorosis is of unfavorable import. 

In secondary anemia the occurrence of eosinophile cells depends 
largely upon the underlying condition, the anemia itself not effecting 
any increase but rather a decrease. There are, however, many 
examples of secondary anemia with marked eosinophilia— e. g., anky- 
lostomiasis. 

Diseases of Lungs. The occurrence of large numbers of eosinophile 
cells in the blood and sputum of asthmatics was first noted by Gol- 
lasch, and has been uniformly confirmed by later observers (Leyden, 
Zappert, Mandybur, Weiss, Gabritschewski), v>^ho have found them 
to vary in the blood of such cases from 9 to 22 per cent. In simple 
emphysema they are not markedly increased, and in pulmonary 
tuberculosis they are usually much diminished. Where tuberculosis 
complicates emphysema, both blood and sputum may, however, show 
an excess of eosinophile cells (Weiss, Aronson and Philip). 

In tuberculosis of lungs or other tissues an absence of eosinophile 
cells from the blood is often observed, and this fact has been of con- 
siderable value in differential diagnosis between this and other condi- 
tions in which normal or increased numbers of these cells are present ; 
yet when tuberculosis is accompanied by cachexia and irregular 
suppuration, eosinophile cells may reappear in moderate numbers. 
Neusser believes that when these cells persist in tuberculosis the out- 
come is usually favorable, since gouty subjects are comparatively 
resistant to this infection ; yet tuberculosis in emphysematous lungs 
is not infrequently seen at autopsy. The eosinophilia following 
injections of tuberculin has already been considered. In subacute 
or chronic tuberculous lesions eosinophile cells are very frequently 
present in the tissues in large numbers. 

In febrile diseases of liver and gastro-intestinal tract the occurrence 
of eosinophile cells in the blood shows no uniformity. They have 
been found moderately increased in cirrhosis of the liver. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 163 

In chronic nephritis the eosinophile cells are apt to reach the higher 
physiological limits. Neusser believes that uremic seizures are regu- 
larly accompanied by increase of these cells in the blood, and Zappert 
and Castellino report such cases. 

In nervous diseases, functional and organic, Zappert found, as a 
rale, a moderate increase of eosinophile cells, without being able to 
substantiate Neusser's classification of neuroses into those with and 
those without eosinophilia. The latter he preferred to regard as 
exceptions to the very general rule. In a distinct sympathetic 
neurosis they were not increased. In general insanity no uniform 
increase has been demonstrated (Zappert, Krypiakiewicz). Jelliffe 
found a moderate increase in one and a total absence of eosinophiles 
in five of twenty cases of general paresis. In Basedow's disease they 
are usually increased (JSTeusser). 

ISTeusser finds eosinophilia in a variety of nervous disorders, the 
psychoses of menstruation, puerperal mania, epilepsy, tetany, Base- 
dow's disease, hemicrania. In acute mania not connected with preg- 
nancy, and in melancholia, Somers found a well-marked and uniform 
eosinophilia. 

Tumors. From observations on twenty-four cases Zappert con- 
cluded that a very uncertain eosinophilia may occur with new- 
growths, especially when cachexia is not advanced. He found 17.76 
per cent, of eosinophiles in one of several cases of lymphosarcoma, 
and a distinct increase in isolated cases of carcinoma. Neusser claims 
that eosinophilia arising in the course of a tumor growth indicates 
metastasis in the marrow, and Beinbach found 60,000 in a case 
of lymphosarcoma with metastasis in the marrow. Feldbausch 
studied the occurrence of eosinophile cells in tumors. He always 
found them in considerable numbers in the growing edges of epithe- 
liomata, less often in carcinomata, while in some lymphosarcomata 
they were very abundant. 

Skin Diseases. Various cutaneous lesions have furnished some of 
the most marked and interesting examples of eosinophilia. While 
the highest numbers of these cells have been found in pemphigus 
(4800), it has been shown by Canon and verified by Zappert that 
the eosinophiles are affected not so much by special forms of cuta- 
neous lesions as by the extent, intensity, and lack of healing ten- 
dency on the part of the lesion. Moreover, it appears that local 
afflux of eosinophile cells occurs in the early and in the less active 
stages of many cutaneous lesions, and is often insufficient to cause a 
general increase in the blood. That many lesions are caused by local 
toxic agents having special chemotactic influence over eosinophile 
cells is indicated by the fact that in pemphigus artificial blisters do 
not necessarily contain the larger numbers of these cells that are 
found in the spontaneous lesions (Kreibich). 

Among the diseases showing high eosinophilia may be mentioned : 
pemphigus, eczema, scleroderma, psoriasis, pellagra,^ lupus, if wide- 
spread, urticaria (60 per cent., Lazarus) (Zappert, Neusser, Canon, 
Tscheleneff, Laredde). 

In the blood of leprosy Gaucher and Bensaude found 8.48 to 28 



164 GENERAL PHYSIOLOGY AND PATHOLOGY. 

per cent., Darier as high as 61 per cent., and Bettman 7 to 18.4 per 
cent. 

In pemphigus Coe reports one case with 12,000 leucocytes and 10 
to 51 per cent, of eosinophile cells, and another fatal case with 6 per 
cent. Euss observed a fatal case in which there was no eosinophilia. 

In zoster' Bettman found a high proportion of eosinophile cells in 
the vesicles, but usually no increase in the circulating blood. 

Sab razes and Mathis followed the changes in the blood in eight 
cases of zoster. The Hb and red cells were unaffected. On the first 
day of the eruption they found leucocytosis 11,780 to 16,740, which 
increased until the third to fifth days, maximum 17,900, and usually 
persisted three to five days longer, disappearing as the vesicles 
began to fade. During desquamation, eighth to twelfth days, there 
was sometimes a second increase (14,880 to 16,120), especially of 
eosinophile cells. All varieties of white cells were in excess, and 
the percentage of poly nuclear cells was rarely above normal. The 
eosinophile cells were usually abundant, 4 to 8 per cent., and once 
reached 20.5 per cent. The vesicles showed progressive increase of 
polynuclear cells until the sixth day, when eosinophile leucocytes 
began to appear in the exudate. 

Post-febrile Eosinophilia. In nearly all forms of acute polynuclear 
leucocytosis an absence of eosinophile cells has been noted. Scarlet 
fever, acute rheumatism, and malaria sometimes furnish notable 
exceptions to this rule. Early in the decline of the febrile process, 
and before the neutrophile leucocytes have greatly decreased, eosino- 
phile cells begin to reappear, and may shortly be found in more than 
normal numbers. The reappearance of eosinophile cells in pneumonia 
and septic processes, etc., has often been found to herald a favorable 
turn in the disease, but usually other favorable clinical symptoms 
are present at the same time. 

In malaria, eosinophile cells usually persist in small numbers 
during the paroxysm, while in the afebrile interval, and in chronic 
cases, a slight eosinophilia exists, and may be a useful diagnostic 
feature of the blood. 

In acute rheumatism they are usually present in moderate num- 
bers during the fever, increase slightly during convalescence, and 
in one of Zappert's cases a relapse was attended with a further 
increase. 

Acute Exanthemata. In scarlatina there is a remarkable exception 
to the usual rule that eosinophiles disappear during febrile leucocy- 
tosis, for in this disease they usually persist and may be markedly 
increased. This peculiarity was first noted by Kotschetkoff, who 
found that the oxyphile cells steadily increase during the fever, reach 
a maximum in the second or third weeks (8 to 15 per cent.), and 
fall to normal in six weeks. In his very severe cases, however, they 
fell more rapidly. Rille found marked eosinophilia in severe cases, 
and Zappert, Silvester, and Felsenthal have added confirmatory 
reports. 

In measles eosinophiles are usually normal or diminished (Zappert, 
Felsenthal, Cabot). 



THE LEUCOCYTES AND LEUCOCYTOSIS. 165 

In some other acute simple erythemata Zappert found distinct 
eosinophilia. 

Gonorrhea. According to Bettman, eosinophile leucocytes appear 
in gonorrheal pus during the first few days of the disease when the 
exudate is largely serous. Here as elsewhere it seems that when the 
stage of exudation of neutrophile cells is reached the eosinophiles 
largely or entirely disappear, to return again during the decline of 
the discharge. This latest contributor also agrees that the involve- 
ment of the posterior urethra and prostate is usually attended with 
a marked increase of oxyphile cells in the discharge, and he finds 
further a similar influence from the involvement of the epididymis. 

Most observers are agreed that the eosinophile cells of the blood 
are increased when they are abundant in the discharge, but not in 
any proportionate degree (Posner, Finger, Pezzoli, Janowsky, Epstein, 
Tscheleneff, Yorbach). Bettman found 25 per cent, in a case com- 
plicated by epididymitis. 

Syphilis. A very uniform increase of eosinophiles accompanying 
cutaneous syphilis was noted by Rille and by Loos, but the observa- 
tions of Miiller and Rieder and of Zappert, though less numerous, 
did not bear out these claims. In a case of congenital syphilis Miiller 
and Rieder found a well-marked increase (12 per cent.). 

Of osteomalacia Neusser finds two types, with and without eosino- 
philia. The latter are usually advanced cases with inflammatory 
changes in the bones and marrow and myelocytes in the blood. The 
former include those cases in which castration has been followed by 
recovery. 

Gout. Neusser first called attention to the high proportion of 
eosinophile cells in the blood of gouty subjects. Although his opinion 
was not supported by extensive reports, it will generally be found 
that in the gouty diathesis the eosinophiles reach Zappert's interme- 
diate or high normal limits. Yet in testing this rule the writer 
soon found that this feature of the blood is of little value in the diag- 
nosis of acute gout, meeting with cases in which the blood contained 
few oxyphile cells. In the irregular manifestations of the diathesis, 
eosinophilia appears to be more uniform but still subject to many 
variations. 

Intestinal Parasites. Infection with various common intestinal 
parasites is accompanied by extreme eosinophilia, as first noted by 
Buckler in 1894. 

In cases infected by oxyuris, Buckler found 19 per cent, of eosino- 
philes ; by ascaris, 16 per cent.; ankylosioma, 72 per cent.; tenia 
medioGanellata, 34 per cent. In most of these cases eosinophile cells 
and Charcot-Leyden crystals are abundant in the feces. 

Ankylostomiasis, however, is not always accompanied by eosino- 
philia or crystals in feces (Ehrlich). In the anemia from hothrio- 
cephalus lotus Schumann found few eosinophiles in the blood. Trichi- 
nosis has lately been added to the list of diseases marked by 
extreme eosinophilia. 

In cases of echinococcus cyst Dargein reports 12 per cent, of 
eosinophile cells. 



166 GENERAL PHYSIOLOGY AND PATHOLOGY. 

Origin and Significance of Eosinophilia. The very diverse 
opinions that have prevailed regarding the origin of eosinophilia can 
only be finally reconciled by holding strictly to the view that eosino- 
phil e cells are derived solely from the eosinophile cells of the bone- 
marrow. That a local multiplication of these cells may occur under 
many circumstances is, however, strongly suggested by their abun- 
dance in certain foci, especially in the skin and mucous membranes. 
Thus, in the absence of general eosinophilia, rich deposits of eosino- 
phile cells are often found in normal tissues, in cutaneous vesicles 
and pustules, in chronically inflamed mucous membranes, in nasal 
polyps and other tumors, and in leprous, tuberculous, and syphilitic 
lesions. Lately they have been found in very large numbers in 
bloody exudates in the pleura (Weiss^). Their abundance in the 
mucosa and exudate of the inflamed bronchi in asthma led Neusser, 
and, on parallel grounds, many others to actively maintain their local 
origin apart from the bone-marrow. In one case of pemphigus with 
marked local and general eosinophilia, Neusser^ is reported to have 
found no increase of eosinophiles in the bone-marrow, but studies in 
this important field are yet entirely inadequate to figure in the dis- 
cussion. In the marrow of cases of malaria showing eosinophilia 
the writer found an increased number of eosinophile cells, while in 
other cases without eosinophilia these cells in the marrow also were 
deficient. Dominici found an excess of eosinophiles in the marrow 
of a rabbit showing marked eosinophilia. 

The exponents of the local origin of eosinophile cells have been 
unable to bring forward evidence to prove that these cells undergo 
mitotic division in the skin or that neutrophile granules are there 
transformed into eosinophile. 

The writer believes that all the phenomena connected with general 
and local eosinophilia can best be explained by the same chemotactic 
principles that are known to control neutrophile cells. From the 
observations on eosinophile cells in gonorrheal pus, in cutaneous 
and serous exudates, and in the blood it appears that inflammatory 
products attract these cells at one stage and neutrophile cells at 
another and more acute stage. As purulent exudates of small extent 
may cause no general leucocytosis — e. g., furunculosis — so, many 
cutaneous lesions with exudates composed largely of eosinophiles 
cause no general increase in the circulation, but when either reaches a 
certain grade the neutrophile or eosinophile cells are drawn from the 
marrow in sufiicient numbers to cause a noticeable increase in the blood. 

Ehrlich finds reason to believe that substances which attract 
eosinophile cells may be derived from the destruction of epithelial cells, 
as seen in the local eosinophilia about the ulcers of lupus after injec- 
tion of tuberculin, froin mucin as in nasal polyps, and from toxins of 
parasites. Michaelis has shown that when lactation is interrupted in 
the guinea-pig many eosinophile cells collect in the breasts ; but in the 
human breast after stagnation of milk Unger found many mast-cells. 

Weiss has recently maintained that local eosinophilia tends to occur 
where there is extensive extravasation of blood, the derivatives of 
hemoglobin being absorbed by the polynuclear cells and deposited in 



THE LEUCOCYTES AND LEUCOCYTOSIS. 167 

the form of eosinophile granules. He bases this opinion on the 
observation of a case of septicemia with hemorrhagic pleural effusion. 
In the blood there were 40 per cent, of eosinophile cells, while in 
the sediment of the exudate 76 per cent, of these cells were found. 
He refers to two other somewhat similar cases reported by Harmser. 

The most comprehensive view of the significance of eosinophilia 
is that of Neusser^ and his pupils, who from extensive observations 
have found evidence that the supply of eosinophile cells in the blood is 
controlled by the sympathetic nervous system, and that eosinophilia is the 
expression of sympathetic nervous irritation. This irritation, they 
believe, may proceed from the generative organs, ovaries, uterus, or 
prostate, disorders of which, with their related neuroses, are usually 
accompanied by eosinophilia ; from the skin, diseases of which have 
furnished some of the best examples of eosinophilia ; from the intes- 
tines, from which the toxemia of parasites and that of gout, which 
Neusser regards as of intestinal autotoxic origin, give rise to marked 
eosinophilia, etc. 

Following out this idea, Neusser has elaborated an extensive 
scheme of the altruistic relations of the viscera in disease, by which 
he is able to correlate nearly all the diseases showing eosinophilia. 
He finds a necessary sequence of events in a case which suffered from 
migraine in youth, pemphigus and asthma in old age, and died from 
cancer of the prostate with general metastasis in the bone marrow. 

Although the recent tendency has been to deny any great impor- 
tance in Neusser^s conception of eosinophilia, it must be remembered 
that it is based on a well-known and far-reaching principle in path- 
ology. While in practice a great many exceptions have been found 
to the rules which he formulated, it will yet be wise to keep them in 
mind in drawing conclusions from eosinophilia. 

Value of Eosinophilia in Diagnosis. In general, the presence 
of a moderate or increased number of eosinophiles in the blood is 
often of value in the diagnosis between a condition in which these 
cells are known to persist as against those in which they are com- 
monly absent. The writer has found situations of the sort most fre- 
quently in the diagnosis between gouty and tuberculous affections. 

Other situations have arisen in the diagnosis between active mala- 
rial and typhoid fevers, scarlet fever and measles, trichinosis and 
rheumatism. 

In prognosis the reappearance of these cells in suppurative pro- 
cesses is undoubtedly a favorable sign indicating the approach of 
defervescence. 

Many clever deductions have been drawn by Neusser and his 
pupils from the behavior of eosinophile cells in the blood, but others 
have not been so successful in this field. 



OCCURRENCE OF MAST-CELLS. 

The knowledge of mast-cells dates chiefly from the studies of 
Westphal (1880) and of Unna, who found abundant collections of 



168 GENERAL PHYSIOLOGY AND PATHOLOGY. 

large mononuclear cells, with large, strongly basophile granules, in 
tumors, and in tuberculous, syphilitic, and other lesions of the skin. 
The occurrence of such cells in tissues has since been described by 
many writers, and it is now accepted that their appearance is favored 
by a considerable variety of chronic disturbances of nutrition in tissues, 
and that they are commonly associated with eosinophile cells. The 
majority of coarsely granular basophilic cells in tissues are not, how- 
ever, identical with the mast-cells of the blood. 

In the blood Canon failed to find them in nine of twenty-two 
healthy subjects, counting 500 to 1000 leucocytes, while in the other 
thirteen cases they yielded an average of 0.47 per cent. In a variety 
of skin diseases (twenty cases) they were slightly more numerous 
(0.58 per cent.), and, in general, were slightly increased when eosino- 
phile cells were abundant. Sherrington found them distinctly 
increased in the blood of moribund cholera patients. Goldhorn 
finds that his method of staining is invariably successful in demon- 
strating mast-cells in normal blood. In cases of severe malaria the 
writer has seen them more abundant in the blood than in any condi- 
tion except leukemia, while in the viscera of such cases large granular 
basophilic cells were unusually frequent. 

^eusser examined a gonorrheal exudate composed exclusively of 
mast-cells, while Wolff reports 5 per cent, of mast-cells in a pleuritic 
exudate. Schmauch found marked increase of mast-cells in the 
blood of rabbits after injections of pyronin. 

In myelogenous leukemia there is, in the majority of cases, mast- 
cell leucocytosis, these cells being here more abundant than in any 
other condition They often outnumber the eosinophile cells (Ehr- 
lich), and must be considered the sole isolated pathognomonic sign 
of this disease. Ehrlich's statement [Die Anaemie, p. 123) that they 
are invariably present in considerable numbers in myelogenous leuke- 
mia may be capable of verification by recent methods, as Michaelis 
finds that the mast-cells of leukemia are much more soluble in water 
than those of normal blood ; but with ordinary methods one may 
sometimes search in vain over thousands of cells in chronic cases. 

Ehrlich believes that mast-cells are derived exclusively from the 
bone marrow, and respond to chemotactic influence from principles, 
however, which are very rarely present in the human organism. 

OCCURRENCE OF MYELOCYTES (EHRLICH'S). 

Although the eosinophile myelocytes and, to a less extent, Cornil's 
very large, pale neutrophile myelocytes are found almost exclusively 
in myelogenous leukemia, the smaller variety of mononuclear neutro- 
phile cells have been shown to occur in the blood in a considerable 
variety of conditions. 

From the many recent reports of the occurrence of a few myelo- 
cytes in the blood it appears that such cells may be swept from the 
marrow by several distinct causes : 

1. AcCOMPANYIIfa THE POLYNUCLEAR LEUCOCYTOSIS OF INFEC- 
TIOUS DISEASES, a considerable number of myelocytes may be found. 



THE LEUCOCYTES AND LEUCOCYTOSIS. 169 

This fact first appeared in the studies of Turk, was emphasized 
through the discovery by Engel of unusually large numbers (12 per 
cent.) in unfavorable cases of diphtheria, and has since been extended 
by others to most severe, acute, and subacute infections. 

Usually the percentage of these cells in polynuclear leucocytosis is 
much lower than in diphtheria, and not being associated with eosino- 
phile cells or mast-cells, it can seldom raise a suspicion of leukemia. 
Nevertheless a difficulty arose with a case of acute leukemia, observed 
by Thomson and the writer, in which the first examination of the 
blood in a case resembling typhoid fever showed leucocytosis and 5 
per cent, of myelocytes. A few days later there were 12 per cent, 
of myelocytes, and at the autopsy the lesions of leukemia were 
demonstrated. Eosinophiles and mast-cells were absent. 

The presence of myelocytes in polynuclear leucocytosis is readily 
explained by the hyperplasia and hyperemia of the marrow. 

2. In primary and secondary anemias of severe or even of 
moderate grade, a few myelocytes have frequently been observed 
(Klein, Krebs, Loos, Hammerschlag, Capps). They are, perhaps, 
most frequently seen in pernicious anemia (Neusser), in the anemia 
of syphilis (Rille), with malignant tumors (Cabot), and in v. Jaksch's 
anemia. It has been supposed that tumors involving the marrow 
would yield myelocytes as well as eosinophiles in the blood, and 
SoUey has recently described a case of sarcoma involving the bone 
marrow in which the blood showed 18 per cent, of myelocytes. 
They have been noted in considerable numbers in rachitis, osteo- 
myelitis, and osteomalacia. 

In all the above conditions the appearance of myelocytes must be 
referred to hyperplasia of red marrow, to mechanical dislodgement of 
marrow cells resulting from structural changes in the marrow or 
hydremic states of the blood plasma, and to chemotactic influences 
which may attract the ameboid myelocytes as well as the adult poly- 
nuclear cells. 

3. After severe mechanical disturbances of the circula- 
tion a few myelocytes may be found in the blood. This rule is 
illustrated by their discovery in the blood of uremia, asphyxia, acute 
mania, etc. (Neusser). The writer has seen a few myelocytes appear 
during antemortem leucocytosis. 

The occurrence of myelocytes in leukemia will be considered with 
that disease. 

LYMPHOCYTOSIS. 

A relative or absolute increase of lymphocytes in the blood is of 
frequent occurrence and has at times important significance. In 
speaking of lymphocytosis, as of eosinophilia, since each of the cells 
concerned represents an independent series, conceptions will be more 
accurate if the actual numbers, as well as the relative proportions, 
are reported. In estimating lymphocytosis it is important to distin- 
guish also between the large lymphocytes and large mononuclear 
leucocytes with faintly basophil e protoplasm. 



170 GENERAL PHYSIOLOG Y AND PATHOLOG Y. 

Physiological Variations. Physiological variations in the pro- 
portions of lymphocytes are observed at different periods of life. 
The first embryonal leucocytes are all mononuclear basophile cells 
(Saxer), but as other varieties of leucocytes make their appearance, 
the proportion of lymphocytes diminishes until, at birth, the healthy 
infant shows 60 to 66 per cent, of these cells. Throughout healthy 
infancy this proportion steadily diminishes until, at the tenth to the 
fourteenth years, the usual percentage is 27 to 30 per cent. 

Pathological Lymphocytosis. Anything which interferes with 
the natural development of the infant retards the progress of this 
change in the proportion of lymphocytes, which is found to be rela- 
tively high in anemic or poorly developed children. Sometimes the 
development of lymphatic tissue reaches an excessive grade, and a 
condition known as " constitutio lymphatica ^^ is established, marked 
by lymphocytosis, with simple hyperplasia of many lymph nodes 
and of the red marrow, by rachitis, and by many other develop- 
mental anomalies. Since Ohlmacher has demonstrated that most 
cases of idiopathic epilepsy are associated with the constitutio lymph- 
atica, it is reasonable to suppose that lymphocytosis is a frequent 
feature of the blood in such cases. The lymphocytosis of Basedow's 
disease should probably be placed in this connection. 

Rachitis is almost always attended with a well-marked increase in 
the number and proportion of lymphocytes in the blood (Rieder, 
Monti, Berggrun). This fact is plainly referable to the lymphoid 
hyperplasia and the hyperemia of the bone marrow in this disease. 

In some tumors E.einbach has reported an extreme diminution of 
lymphocytes, only 0.6 per cent, being present in one case of lympho- 
sarcoma colli. This result is referred by Ehrlich to closure of the 
lymph paths by sarcomatous growth. In many lymphomata, how- 
ever, there is marked uniform lymphocytosis, and it would appear 
that these neoplasms when leaving the lymph paths free induce 
lymphocytosis. As the more malignant tumors obliterate lymph 
paths, some inference regarding prognosis may be derived from the 
presence or absence of lymphocytosis in these cases. Various other 
types of sarcoma are frequently associated with lymphocytosis and 
there are on record several cases of sarcoma associated with lymphatic 
leukemia. (See Leukemia.) In most splenic tumors there is relative 
or absolute lymphocytosis (Miiller and Rieder, Weiss^). On the 
other hand, after splenectomy in animals, prolonged lymphocytosis 
is usually observed (Kurloff). In man, both mononuclear and poly- 
nuclear cells are usually much increased after this operation. 

The lymphocytosis of infectious diseases is probably always associated 
with acute hyperplasia of the lymphatic structures. 

In typhoid fever the hyperplasia is most marked in the abdominal 
nodes and spleen, but may become more general. There is in this 
disease a relative lymphocytosis, which after the first week usually 
increases until there is a high percentage of lymphocytes. The 
writer has found a uniform relation between the lymphocytes in the 
blood and the grade of lymphatic hyperplasia found at autopsy. In 
one case the examination of the blood led to a strong suspicion of 



THE LEUCOCYTES AND LEUCOCYTOSIS. 171 

lymphatic leukemia, and at autopsy the mesenteric glands were of 
unusually large size, and the edges of the partly necrotic intestinal 
ulcers rose 1.5 cm. above the mucosa. 

In the infectious diseases of children a well-marked lymphocytosis, 
together with increase of neutrophile cells, is so common that it 
should occasion no surprise, and points merely to a special involve- 
ment of the lymphoid tissues. 

In diphtheria a close relation between lymphocytosis and lymphatic 
hyperplasia was noted in some of the writer's cases. In others, 
however, the lymphocytes, though increased, were not in relatively 
high proportion, while the cervical lymph nodes were much enlarged. 

In bronchopneumonia Cabot reports a case with 94,600 leucocytes, 
69 per cent, of which were lymphocytes 

In lohooping-Gough during the convulsive period Meunier found 
the neutrophile cells doubled, but the lymphocytes quadrupled in 
number. 

During the course of measles, at the close of scarlet fever or small- 
pox, and during prolonged lysis in ^pneumonia (Klein), a relatively 
high proportion or increased number of lymphocytes is usually 
observed. 

In the less acute diarrheas of infancy the lymphocytes are usually 
slightly, and sometimes very much, increased over the high propor- 
tions normally existing at that age, as a result of the hyperplasia 
and irritation of the intestinal lymphoid structures (Weiss^). Diges- 
tion leucocytosis is also for the same reason largely a lymphocytosis 
(Rieder). In the initial or persistent hypoleucocytosis sometimes 
observed in infectious diseases (pneumonia, diphtheria) the remain- 
ing cells are chiefly lymphocytes. 

Of chronic diseases affecting the lymphatic tissues both tuberculosis 
and syphilis are frequent causes of lymphocytosis. 

In various forms of pulmonary and visceral tuberculosis the leuco- 
cytes are usually normal or diminished in number and the majority 
of those remaining are lymphocytes, a relation which is, of course, 
altered when from any cause polynuclear leucocytosis is established. 
The condition of the blood is here in accord with the histological 
character of the visceral lesions in which the infiltration with " round 
cells '' is a prominent feature. 

Lymphatic anemia is a term applied by Neusser to a rather char- 
acteristic group of cases in which there is chlorotic anemia, lympho- 
cytosis, and, usually, evidence of tuberculosis. Rieder could not 
agree with Neusser that most cases of chlorotic anemia with increase 
of ~ lymphocytes are associated with tuberculosis and are of less 
favorable prognosis. The writer finds that the chlorotic anemia of 
tuberculosis, as a rule, shows absence of eosinop)hile cells as well as 
increase of lymphocytes. 

Injections of tuberculin are usually followed by fever and lympho- 
cytosis, which may be referred to irritation of inflamed tuberculous 
lymph nodes (Ehrlich). 

In congenital and in secondary acquired syphilis, it has been shown 
by Bieganski, Rille, Anc, and others, that there is uniform and con- 



172 GENERAL PHYSIOLOGY AND PA THOLOGY. 

siderable lymphocytosis, which must here again be referred to the 
involvement of lymph nodes. 

The presence of an increased proportion of lymphocytes in some 
cases of scurvy and hemophilia, has been observed by Neusser, and 
the same feature is recognized by Ehrlich in many severe anemias. 
In anemia infantum pseudoleiikemica the very numerous leucocytes 
are principally large mononuclear cells. In jjernicious anemia a 
considerable leucocytosis may consist chiefly of lymphocytes. 

Experimental Lymphocytosis. Experimental lymphocytosis has 
been produced by injections of tuberculin and of extract of carcino- 
matous tumors by Grawitz, who refers this effect to the lymphogogic 
action of these agents. Waldstein reports lymphocytosis in rabbits 
from pilocarpine, which the Avriter finds to induce in rabbits only 
a relative increase of lymphocytes by diminution of polynuclear 
cells. 

In the origin of lymphocytosis Ehrlich finds that mechanical rather 
than chemotactic influences are chiefly or wholly concerned ; but 
reasons have already been given for doubting the entire truth of this 
conclusion, since the lymphocytes possess ameboid properties and 
may be sensible to chemotactic influences. 

The histology of tuberculous and syphilitic lesions, especially the 
" lymphoid tubercle '^ and chancre, indicate that there are some con- 
ditions which gather large numbers of these cells from the blood and 
lymph nodes. Janowsky's experiments in which large collections 
of lymphoid cells were shown to gather at the site of injection of tur- 
pentine, etc., point to the same conclusion. In all of these situa- 
tions, however, the lymphocytes, like eosinophil e cells, seem to 
follow entirely different rules from those governing neutrophile cells 
— a fact which emphasizes the importance of Kanthack^s classifica- 
tion of lymphocytes and eosinophiles as celomic, the neutrophile as 
hemic cells. 

Relation of Lymphocytosis and Eosinophilia. It is of interest 
to note that a peculiar relation seems to exist between the appearance 
in blood and tissues of lymphocytes and eosinophile cells. ^Neither 
are apt to appear when neutrophile cells are prevailing in blood or 
exudate, but either may be found in the less acute exudative 
processes. The sequence of lymphocytosis followed by eosinophilia 
is especially clear after the injection of tuberculin (Grawitz) and after 
splenectomy in animals (Kurloff). Many other less patent examples 
of this relation may be noted by comparing the conditions showing 
lymphocytosis or eosinophilia, as above detailed. 

Large Mononuclear Leucocytes in Lymphocytosis. In the 
majority of cases reported as showing lymphocytosis no distinction 
has been made between lymphocytes and large mononuclear leuco- 
cytes. Yet there is considerable evidence to show, as Ehrlich 
believes, that these cells represent separate series, and in some con- 
ditions it is the large mononuclear leucocytes and not the lympho- 
cytes which are increased in number. This fact has been noted in 
V. Jahsch^s a,nemia, especially by Hock and Schlesinger ; in rachitis 
by Rieder ; in syphilis by Rille ; and after smallpox and scarlet 



THE LEUCOCYTES AND LEUCOCYTOSIS. 173 

fever by Felsenthal.^ It is sometimes distinctly seen after splenec- 
tomy In the cases of acute lymphemia, described by Frankel and 
others, the majority of cells are of large size. The significance of an 
increase of large mononuclear cells apart from lymphocytes cannot 
at present be stated. 

Bibliography. 

EosiNOPHiLiA, Lymphocytosis, etc. 

Anc. Diss., Wratch, 1895. No. 5. 
Aronson, PhiUip. Dent. med. Woch., 1892, No. 3. 

Bettman. Archiv f. Derm. ii. Syph., Bd. 39, p. 227. Miinch. med. Woch., 
1898, p. 1229. 

Bieganski. Archiv f. Derm. u. Syph., 1892, i. 

Buckler. Munch, med. Woch., 1894, Nos. 2-3. 

Cahot. Boston Med. and Surg. Jour., vol. cxxxiv. p. 4. 

Canon. Deut. med. Woch., 1892, p. 206. 

Capps. Amer. Jour. Med. Sci., July, 1896. 

CasteUino. Gaz. d. ospedah, 1891, p. 476. 

Coe. Amer. Med., 1902, p. 1092. 

Dargein, Tribondeau. Compt. Rend. Soc. Biol., 1901. 

Darier. Annal, de Dermat., 1896, p. 842. 

Dominici. Compt. Rend. Soc. Biol., 1900, p. 73. 

Engel. Deut. med. Woch., 1899, pp. 118, 137. 

Epstein. 65th Versl. d. Naturfors., Nurnberg, 1893. 

Etving. N. Y. Med. Jour., vol. Ixvi. p. 37. 

Feldhausch. Yirchow's Archiv, Bd. 161, p. 1. 

Fehenthal. ' Archiv f . Kinderheilk., 1892, p. 86. ^ i]j[±^ 1593^ p. 78. 

Finger. Blennorrhoea d. Sexualorgane. 

Frankel. Deut. med Woch., 1895, p. 623. 

Gabritschewski/. Archiv f. exper. Path., Bd. 28 

Gollasch. Fort. d. Med., 1889, p. 361. 

Gaucher, Bensaude. Annal. de Dermat., 1896, p. 204. 

Hammerschlag. Berl. klin. Woch., 1894, p. 793. 

Hock, Schlesinger. Beitrage z. Kinderheilk., 1892. 

Harder. Jour, of Tropical Med., 1901. 

Janowskij. Cent. f. Path., 1892. Ziegler's Beitrage, Bd. 15, p. 128. 

Jelliffe. N. Y. State Hospital Bull., ii. p. 397. 

Klein. Volkmann's Yortrage, 1893, No. 87. 

Kotschetkoff. Cent. f. Path., 1892. 

Krebs. Inaug. Diss. Berlin, 1892. 

Kreibich. Archiv f. Derm. u. Syph., Bd. 50, p. 225. 

Krypiakiewicz. Wien. med. Woch., 1892, No. 25. 

Kurloff. Abstract by Ehrlich, Die Anaemie, i. 

Laredde. Annal. de Dermat., 1898, p. 1016. 

Ley den. Deut. med. Woch., 1891, No. 38. 

Loos. Wien. klin. Woch., 1892, p. 261. 

Mandybur. Wien. med. Woch., 1892, Nos. 7-9. 

Meunier. Compt. Rend. Soc. Biol., 1898, p. 103 

Michaelis. Cited by Ehrlich, Die Anaemie, i. p. 112. 

Muller, Rieder. Deut. Archiv klin. Med., Bd. 48, p. 105 

Neusser. ^ Wien. klin. Woch., 1892, No. 4. 2 cited by Kreibich. 

Ohlmacher. Bull. Ohio State Hospital, 1898. 

Pezzoli. Archiv f- Derm. u. Syph., Bd. 35. 

Posner. Diagnostik d. Hautkrankh. 

Reinbach. Langenbeck's Archiv, Bd. 46. 

Rille. Archiv f. Derm. u. Syph., Bd. 24, p. 1028 

Russ. Amer. Med., Mar. 15, 1902. 

Sabrazes, Mathis. Rev. de Med., 1901, p. 251. 

Saxer. Anatomische Hefte, 1896, Bd. 6. 

Schaumann. Zur Kenntniss d. Bothriocephalus Anaemie, Berlin, 1894. 

Schmauch. Yirchow's Archiv, Bd. 156, p. 231. 

Sherrington Proc. Roval Soc, 1894, vol. Iv. p. 161 



1 74 GENERAL PHYSIOL OGY AND PA THOL OGY. 

Silvester. St. Bartholomew's Hospital Rep., vol. xxxii. 

Somers. N. Y. State Hospital Bull., vol. i. p. 75. 

Thomson, Ewing. N. Y. Med. Record, vol. liii. p. 333. 

Tscheleneff. Annal. de Dermat., 1898, p. 1152. 

Turk. Blutuntersuch. bei Infectionskrankh., 1898. 

Unger. Cited by Ehrlich, Die Anaemie, vol. i. p. 112. 

Unna. Monatsch. f. prak. Dermat., Bd. 18. 

Vorbach. Diss. Wlirzburg, 1895. 

Weiss. ^Cent. f. inn. Med., 1899, p. 97. ^Wien. med. Presse, 1891, p. 1538. 

Westphal. Ehrlich' s Gesam. Mitt. 

Wolff. Miinch. med. Woch., 1902, p. 226. 

Zappert. Zeit. f. klin. Med., Bd. 23, p. 227. 



CHAPTEE y. 

DEVELOPMENT OF BLOOD CELLS. 

While the mode of origin of the first blood cells of the embryo 
has been fully determined, the alterations in the process which 
supervene during late fetal and adult life still remain an obscure and 
difficult problem. It becomes necessary, therefore, to consider sepa- 
rately the formation of blood cells at different periods of intrauterine 
and extrauterine life. 

ERYTHROCYTES. 

Formation of Red Cells in the Embryo. In early embryonal 
life the formation of red cells in isolated groups of mesodermal cells 
in the '^ vascular area '' of the chick was first noted by Pander, who 
named these foci " blood islands." The process was later studied 
more closely by His, Remak, Kolliker,^ Wissosky, Klein, Strieker, 

Fig. 31. 





Theory of endoglobular formation of red cells. (Schiifer.) 

and others. From their researches it appears that the first blood 
cells of vertebrates are formed by the appearance of Hb in some of 
the cells of the mesodermal cords which go to form the first capil- 
laries. Upon the formation of the vessel these cells lie free in the 
lumen as nucleated red blood cells. Both the vessel wall and the 
primitive erythrocytes are thus derived from the same group of cells. 
Theory of Endoglobular Formation of Red Cells. In many mammals 
all the early red cells are nucleated, but in some (rat, guinea-pig) 
many non-nucleated red cells are present at an early stage, although 
in the human embryo they appear certainly only after the fourth 
week and form only 25 per cent, of the red cells at the fourth 
month. The formation of the first non-nucleated red cells has been 



176 GENERAL PHYSIOL OGY AND PA THOL OGY. 

studied by Schafer, Ranvier, Hayem, and others, who describe in the 
rat and guinea-pig the appearance in certain large connective tissue 
cells (angioblasts, hematoblasts, cellules vasoformatives) of disks and 
globules of hemoglobin, which, by subdivision of the body of the 
cell, become non-nucleated red blood cells. These red cells soon 
come to lie free in a central cavity within the cell, which is itself 
transformed into a young capillary. According to this theory, the 
red disks are not cells, but fragments of cells of endoglohular origin, 
while nucleated red cells have a different significance, being formed by 
mitotic division of other nucleated red cells. With the development of 
the lymphatic system and liver, the intracellular formation of red 
cells is said to cease, and few or no traces of it have been described 
in most mammals at birth. Kuborn and Malassez, however, describe 
the formation of red cells in the late embryonal liver and marrow 
through gemmation of the giant cells of these organs. 

The theory of intracellular formation of blood disks has not been supported 
by more recent investigations. Spuler and Saxer find no traces of such a 
process, regarding the vasoformative cells of Ranvier as endothelial cells 
which have become separated from the delicate young vessels, and have carried 
with them some of the red cells of the vessel. In the adult marrow such cells 
have not been fully identified. Recently, however, Francois and Poljakoff 
have attempted to substantiate the theory of endogenous red-cell formation. 
Poljakoff placed cover-glasses separated by a capillary space beneath the skin 
of guinea-pigs for twelve to twenty days. The glasses and inclosed cells were 
immersed in osmic acid and stained by carmine. In such specimens he 
describes the formation of red cells and elaboration of Hb by the linin sub- 
stance of the nuclei of leucocytes and fibroblasts. He says nothing of the 
difficulty of recognizing Hb under such conditions, but is certain that the 
acidophile staining masses are not englobed fragments of red cells. 

In later embryoncd periods the process of development of red cells 
is very similar to that in extra-uterine life. 

Mode of Origin of Red Cells in Late Embryonal and Extrauterine 
Life. That the nucleated red cells of the marrow multiply by in- 
direct division of other nucleated red cells was first stated by Biz- 
zozero,^ and has been accepted by most histologists. Bizzozero, 
however, claimed that the large nucleated red cell of the adult 
marrow is the most primitive cell in the body capable of producing 
erythrocytes, believing that the intermediate stages between the 
embryonal wandering cell and the colored erythroblast have been 
lost in later embryonal life ; but it has since been shown to the satis- 
faction of most authorities, that the series of mitoses leading to the 
production of red disks begins in colorless cells antecedent to the 
large nucleated red cells, and which are only very slightly different 
from the original mesoblastic cell of the embryo. It thus appears 
that the formation of nucleated red cells in the adult is practically 
the same as in the embryo and that at all periods of life the red cell 
is the product of several series of mitoses of a colorless mesoblastic 
cell. The difficulty of tracing this series from the large nucleated 
red cell to the colorless mesoblastic '' mother cell ^^ in the marrow 
has given rise to the diverse opinions now held regarding the ulti- 
mate development of red corpuscles. 



DEVEL0P3IENT OF BLOOD CELLS. 177 

As to the exact morphology of the original erythroblasts of adult 
marrow J opinions are more or less at variance, but it is agreed by 
Neumann/ Eindfleisch, Obrastzow/ Malassez, Howell, Lowit/ 
Miiller, and many others, that it is a large mononuclear cell, larger 
than the ordinary nucleated red cell, with pale nucleus and without 
hemoglobin, and it is usually described as lacking a nucleolus. 
From these " embryonal " cells are derived, by mitotic division, two 
or more series of cells which gradually approach the type of the 
nucleated red cell, which is rich in hemoglobin and whose nucleus 
is compact and pyknomorphous. 

Among dissenting opinions may be mentioned the conclusions of Foa, 
according to whom the red cells are derived from the giant cells of the marrow, 
spleen, and liver, and the theory of Hayem,'^ partially accepted by Afanissiew 
and Pouchet, that the red disks are derived from the blood plates. 

Regarding important details in the origin and relation of the forma- 
tive erythroblasts, opinions are also widely at variance. 

Lowit describes in the marrow, spleen, and lymph nodes, two separate series 
of colorless cells which produce, one, leucocytes, the other, red cells. The 
cells of these two series differ in the structure of the nucleus, in the fact that 
one type (leucoblasts) exhibits ameboid and phagocytic activity, and in their 
method of division, the erythroblasts multiplying by indirect division, the 
leucoblasts by a modified form of karyokinesis described as divisio indirecta per 
granula. According to Lowit the red cells are derived from the erythroblasts 
after these have reached the circulation from the lymphoid tissues, 

Bizzozero'- describes the primitive ery throb! ast as separate from the leuco- 
blast, both in morphology and especially in its relation to the bloodvessels of 
the marrow. While numerous nucleated red cells in mitotic division are 
found, according to Bizzozero, in the masses of cells lying within the capil- 
laries of the marrow of birds, intervascular tissue is entirely free from such 
cells. The capillary network of the marrow is, therefore, an endovascular 
blood gland. This observation has been verified by Torre, Salvioli, and Denys, 
for nucleated hemoglobin-holding cells, but other authors trace the erythro- 
blasts back to colorless cells, which are not invariably intravascular. In man, 
however, while the erythroblasts lie closer to the lumen of the capillary than 
do the leucoblasts, the walls of the sinuses are incomplete and the islands of 
nucleated red cells are found in the midst of masses of leucoblasts (Muir). 

H. F. Miiller describes a common form of mother cell for both red and 
white blood cells. By their indirect division are produced (1) cells which 
resemble the original, (2) mononuclear leucocytes, and (3) nucleated cells 
which develop hemoglobin and by the gradual disappearance of their nuclei 
become the non-nucleated red blood disks. 

Denys believes, with Lowit, that there are two separate developmental 
series of leucoblasts and erythroblasts, each of which multiplies by mitosis, 
and is originally colorless. Both are ameboid, but the erythroblasts are very 
slightly so. Denys, like Bizzozero, finds that the leucoblasts lie in the cords 
outside the vessels of the marrow, while the erythroblasts are found within 
the vessels. 

Hayem believes the red blood disks to be derived from the blood plates of 
Bizzozero, which he therefore calls " hematohlasts." He claims to have seen 
all transition forms between blood plates and red blood cells, and finds that 
when blood formation is unusually active the blood plates and the transition 
forms are more abundant. In regard to many details of the origin of blood 
plates and their transformation into red cells, Hayem was unable to reach 
satisfactory conclusions. 

Naegeli traces the progenitors of the erythrocyte back to large and small 
non-granular cells free from Hb, with reticulated oval nuclei, but without 

12 



178 GENERAL PHYSIOLOGY AND PATHOLOGY. 

nucleoli. Except for the absence of nucleoli this description applies exactly 
to large and small lymphocytes. 

Pappenheim argues strongly in favor of the existence in both embryonal 
and adult marrow of a common cell of origin of both red cells and leucocytes. 
Thi^s cell he describes as indistinguishable morphologically from the large or 
small lymphocytes. His conclusions are based on theoretical considerations 
and on a study of embryonal and adult marrow submitted to a great variety o± 
staining methods. He claims to find all transitional stages between lymphocytes 
and megalocytes on the one hand, and granular leucocytes on the other. 
From this primitive lymphocyte are developed the differentiated lymphocyte 
of the circulation, which is incapable of further change and always remains a 
lymphocyte, while from other types of metaplasia are developed hemoglobin- 
iferous cells and granular leucocytes. 

It seems at present impossible to decide how much credence must be given 
to claims that it is possible to trace hemoglobiniferous cells in the adult back 
to cells which are entirely free from Hb, and which resemble lymphocytes. 
The writer hesitates to accept these claims, because simple but highly difi'er- 
ential staining (hematoxylon and watery eosin) has, in his hands, always cut 
off the hemoglobiniferous cells of the marrow quite distinctly from those 
which are free from Hb. 

To summarize the work m this field, it may be said that we do not 
know certainly whether any common cell of origin of red and white 
blood corpuscles exists in the late embryo or adult, or whether these 
corpuscles are derived from completely separate series. The late 
contributions favor the existence of a common mother cell for both 
groups, persisting at least into late embryonal life. 

The Transformation of Nucleated Red Cells into Blood Disks. To 
that minority of observers who believe that the red blood disks are 
derived from other sources than the nucleated red cells, the task of 
explaining the disappearance of all trace of the nucleus presents 
no difficulties. Among the majority of writers who accept the origin 
from nucleated cells, the theories regarding the disappearance of the 
nucleus are various, but none has been fully demonstrated. 

Kolliker,^ Bizzozero,^ Neumann,^ Lowit, Foa, and many recent 
observers believe that the nucleus gradually disappears in the cell. 
The difficulty in accepting this opinion lies in the fact that while red 
cells with rather small nuclei are abundant in red marrow, the final 
stages of the disappearance of the nucleus are traced onty with diffi- 
culty ; yet Schmidt, Spuler, Israel and Pappenheim, and Masslow, 
claim to have found these final stages in abundance. Ehrlich believes 
that the nucleus of the normoblast is extruded, while that of the 
megaloblast fades within the cell. 

Rindfieisch first, and later Howell, described fully the shrinkage and final 
extrusion of the compact nuclei of red cells in man, mammals, and amphibia. 
Van der Stricht, Kostianecki,^ Saxer, Albrecht, Disse, Muir, and others, find 
that after considerable shrinkage the nucleus may become compact and homo- 
geneous or may be fragmented, but it is eventually extruded, and either breaks 
up in the plasma or is englobed by leucocytes, giant cells, or endothelia. The 
significance of this somewhat remarkable phenomenon has not been fully 
demonstrated. The opponents of this theory claim that free nuclei are seen 
in sufficient numbers to account for the production of many red cells, only in 
smears of the marrow, but scantily in sections. The writer finds this objection 
valid, unless the destruction of extruded nuclei is more rapid than we have 
any good reason to believe. 

As an antithesis to the " extrusion " theory, Malassez, Fellner, and Duval 
believe that the nucleated red cell extrudes a portion of its substance in the 



DEVELOPMENT OF BLOOD CELLS. 179 

form of a red disk entirely free from nuclear material, but the histology of the 
marrow offers insuflacient ground for the belief in such a process. 

EngeP holds that megaloblasts produce megalocytes by gemmation, leaving 
normoblasts, from which the nuclei are extruded. Mondino and Sala find 
evidence that the nuclear material finally diffuses along the periphery of the 
cell, where it undergoes a chemical change which causes it to lose its affinity 
for basic dyes. Obrastzow"'* also believes that the nucleus persists in diffuse 
form in the dist, and that it may reappear as a result of postmortem processes. 
Finally, Bottcher and Brandt claim that the nucleus persists and may be 
demonstrated in the normal red cells by certain staining methods, while Wool- 
dridge and Botazzi and Capelli, by chemical analysis, are always able to 
demonstrate nuclear material in the red cells. 

While the weight of opinion and evidence seems to favor the 
gradual fading of the nucleus within the cell^ and while it can hardly 
be denied that extrusion frequently occurs, there is abundant evidence 
to show that the red cell is not entirely devoid of nuclear material. 
The chemical analysis of the stroma of these cells decidedly favors 
the presence of nuclear elements (Lilienfeld^ Wooldridge); the appear- 
ance of degenerating cells strongly suggests a nuclear remnant, and 
the employment of recent stains — neutral red, polychrome blue — 
frequently yields the specific reaction of chromatin in the centres of 
slightly altered red cells The recent studies of Maximow indicate 
that while the bulk of the nucleus is extruded, a portion remains in 
finely granular form and imparts a basic staining quality to the 
centres, especially of young red cells. 

Seats of Formation of Red Cells, (a) In the early embi^yo the pro- 
duction of red cells follows the development of capillary bloodvessels 
in many tissues. Very soon the rudimentary liver and lymph nodes 
make their appearance and in them the function of red-cell formation 
is gradually concentrated. 

(6) In the fully developed embryo, the majority of investigators 
locate the chief formation of red cells in the liver, to a less extent in 
the spleen, while the bone-marrow, which is at first less prominent 
in this process, gradually absorbs the function, and in the human 
fetus at birth represents its chief seat. 

In most infants at birth, however, the liver, and less constantly 
the spleen, are found to contain many nucleated red cells, while in 
some cases the proportion of these cells in the liver is very large and 
numerous small collections of them may be found scattered along the 
portal capillaries. 

(c) In Extrauterine Life. The fact that the red marrow is probably 
the exclusive depot of formation of red cells in the adult was discov- 
ered almost simultaneously in 1868 by Neumann^ and by Bizzozero.^ 

This original claim has been uniformly substantiated by those 
later observ^ers who recognize as erythroblasts only those cells which 
contain a trace of Hb. Others, as Lowit and Mliller, Gibson, Foa, 
and Saxer, who trace the red cells back to colorless cells, regard all 
lymphoid tissues as probable sources of erythroblasts. 

In -pathological conditions it has been shown that the spleen (Bizzo- 
zero,^ Neumann, 1 Howell) in the human adult may resume its 
embryonal function of red-cell formation, as indicated^ by the pres- 
ence of many nucleated red cells. Under similar conditions it has 



180 GENERAL PHYSIOLOGY AND PATHOLOGY. 

been shown that the limits of red marrow, normally confined to the 
flat bones, ribs, vertebrae, and upper and lower thirds of the long 
bones, may be extended throughout nearly the entire cayities of 
all bones except those of the feet (Xeumann, Litten and Orth, 
Bizzozero and Salyioli). 

In infancy, and up to the sixteenth year, the cavities of all bones 
contain almost entirely red marrow, but there are considerable varia- 
tions in the proportions of lymphoid and fat tissue in the shafts of 
the long bones. It is probable that in most healthy infants the 
formation of red cells is already limited to the lymphoid marrow, 
but considerable numbers of nucleated red cells, often grouped in 
islands, are rather frequently to be found in the spleen and liver of 
apparently healthy asphyxiated infants. In the acute and chronic 
anemias of infancy and childhood, the facility with which the spleen 
and liver resume their former role of red-cell production partly 
explains the special involvement of these organs in such diseases. 



LEUCOCYTES. 

Development of Leucocytes. The earliest indications of the 
formation of leucocytes are seen in the presence of primary wander- 
ing cells, of mesodermal origin, which are found principally in the 
loose connective tissues of the early embryo. The specific quality 
of these wandering cells must stand as one of the fundamental facts 
connected with the development of blood cells. Though of mesoder- 
mal origin they are from the first quite distinct in morphology and 
apparently in function from the capillary endothelium and fixed 
connective tissue cells. The primary wandering cells are of large 
size — ^a to ^a (Saxer) — with a single large nucleus containing one 
or more nucleoli and with a moderate quantity of finely granular, 
slightly acidophile protoplasm. Their development has been traced 
by H. E. Ziegler to masses of mesodermal cells surrounding the 
cords from which the capillaries are formed. It thus appears that 
the parent leucocytes lie originally outside the vessels, into which they 
make their way by virtue of ameboid powers. 

The identity of the primary leucocytes with the primary wander- 
ing cells has been generally accepted, but Schmidt, Bonnet, and 
others, claim that leucocytes are derived from the capillary endothe- 
lium. The weight of evidence, however, is much against this view, 
which inserts the highly specialized endothelial cell as a transition 
stage between the primary mesodermal cell and the leucocytes. An 
isolated position also is assumed by v. Davidoff, Maurer, Beard, and 
others, who believe the leucocytes to be direct derivatives of the 
epithelial cells, principally of the intestine. This view is based upon 
the appearance of lymphocytes in and between the epithelial cells 
lining many mucous surfaces, which has been repeatedly and fully 
explained as an infiltration by leucocytes, not a production of new 
lymphocytes from these cells (Saxer). 

Beard very positively maintains that in Raja the first leucocytes 



DE VEL OPMENT OF BL OD CELLS. 181 

are found in the epithelial masses of the thymus at a stage of develop- 
ment (17 mm.) when no leucocytes are seen in any other tissue. He 
describes the stages of transformation of these epithelial cells into 
leucocytes. This is Kolliker's opinion, first expressed in 1846. 

The white blood cells of vertebrates make their appearance in the 
circulation only after the development of an extensive vascular 
system and long after the red-cell formation has been fully estab- 
lished. In the lower vertebrates their absence has been noted nine 
weeks (Ziegler^) after the appearance of red cells, but Hay em found 
them in frogs' blood thirty-four days after the appearance of red 
cells. The time of their appearance in the blood of the human 
embryo has not been accurately fixed. Gulland finds leucocytes in 
lymph vessels in the human embryo of one and one-half inches in 
length. In form the earliest leucocytes of the embryonal circulation 
are the small and medium-sized basophilic lymphocytes. 

Process of Development of Leucocytes from Primary Wandering Cells. 
Most observers find that the primary wandering cells produce bv 
mitotic division one or more generations of colorless cells which 
gradually approach in morphology the early basophilic leucocytes of 
the circulation. Most of the obscurity which still surrounds the 
early development of red and white blood cells is connected with 
this stage of the process, and the numberless conflicting opinions 
have resulted from the different interpretations placed upon the inter- 
mediate stages between primary wandering cells and circulating blood 
cells. 

Denys, Lowit/ Ziegler,^ v. d. Stricht, and others, claim that red 
cells and leucocytes develop from separate series of cells which have 
become differentiated from the primary mesodermal cells with the 
first appearance of blood and bloodvessels. 

Kostianecki/ Miiller, Schmidt, Saxer, Pappenheim, and others, 
believe that the primary wandering cell persists in the blood-forming 
organs as the parent of both red and white cells. 

It is not impossible to partially reconcile these opposing views. 
While the exhaustive studies of Saxer seem to leave no room to 
doubt the common origin of embryonal red and white cells, it by no 
means follows that the blood cells of the adult may be traced to a 
common origin. Several generations (three to four, Saxer), each 
multiplying by indirect division, are required before the primary 
wandering cell is transformed into red cells or leucocytes. It is 
quite possible that the first members of the series, including the 
primary mesodermal cells, long persist in the embryo, but disappear 
in the adult, in whom, therefore, no common cell of origin of erythro- 
cytes and leucocytes can be demonstrated. 

A review of the principal minute studies in this field seems to the 
writer to warrant the above general conclusion in regard to the rela- 
tion of red and white blood cells. That all blood cells of the embryo 
can be traced to a common origin seems to be fully proven. Although 
the exhaustive studies of Denys, v. d. Stricht, and Lowit were largely 
upon embryonal tissues, the morphological criteria on which they 
separate primary leucoblasts from erytliroblasts do not appear suffi- 



182 



GENERAL PHYSIOLOGY AND PATHOLOGY. 



cieiitly distinct to convince other observers, while the demonstration 
by Saxer and others of earlier mitotic cells in the same embryonal 
tissues seems to show that the common cell of origin persists in the 
fetal liver. Miiller's studies of leukemic blood, in which he seems 
to have traced leucocytes and red cells to a common origin in the 
adult, indicate that this pathological condition involves a reversion 
to the embryonal type of blood formation, but does not prove that 
a common mother cell of both red and white blood corpuscles per- 
sists in the normal adult marrow. (Fig. 32.) 



Fig. 32. 



Prim arv n 'a n de rln a 
cell . ' 



Adult marrow 



£r/i b n o n ai Li ver etc. 
Bi-bappears in la.te/beffflHfe 



Saxer's fl A>rder 




T There is a constantly increasing number of studies which have led to the 
conclusion that there is a developmental relation in the adult between all 
colorless blood cells, and that the indifferent lymphocyte is their common pro- 
genitor. The views of Naegeli and Pappenheim have already been considered 
(p. 177). 

Wolff describes the indifferent lymphocyte as larger than the small lympho- 
cyte of the blood, with round or slightly indented nucleus and non-granular 
cytoplasm which is less basophile than the nucleus, while in the differenti- 
ated lymphocyte the cytoplasm is more basophile than the nucleus. Domiuici 
thinks the primitive lymphocyte is indistinguishable, morphologically, from 
the small lymphocyte of the blood. From an extensive study of the inflamed 
omentum he concludes that polynuclear neutrophile cells develop both from 
myelocytes, and from lymphocytes without passing through the myelocytic 
stage. The myelocytes are developed from the smaller homogeneous basophile 
cells of the marrow. 

Cellular Division in the Development of Leucocytes. Since the full 
demonstration by Flemming of numerous mitotic figures in the cells 
of the lymph follicles, karyokinesis has been accepted as the chief 
method, and many claim it to be the only method, of multiplication 
of leucocytes. 



DEVELOPMENT OF BLOOD CELLS. 183 

This view has been actively combated by Lowit, who finds that while erythro- 
blasts multiply by mitosis, leucoblasts follow a modified form of the process 
which he calls divisio indirecta per granula. This author has very ably and 
successfully defended the importance of direct division in mammals and lower 
vertebrates, and subsequent writers have admitted that this method is of 
*'very widespread''" (Saxer) occurrence among leucocytes. Direct division 
appears to be of special importance in the development of the giant cells of 
the embryonal liver and adult marrow, which play an important but somewhat 
obscure part in blood formation. Indirect fragmentation is a term applied to a 
somewhat peculiar modification of the usual process of nuclear division 
described by many authors, especially by Arnold.^ 

While the formation of leucocytes occurs principally in the blood- 
forming organs, many have found in the circulating blood, and espe- 
cially in the lymph, evidences of active multiplication by mitosis and 
more frequently by amitosis (Spronk and Prins, Lowit,^ Wertheim). 

Sites of Origin of Embryonal Leucocytes. Before the leucocytes 
begin to appear in the circulation mitotic figures are abundantly seen 
in the primary wandering cells in various situations. These are 
gathered in groups, first in the loose connective tissues of various 
regions, where lymph nodes subsequently develop ; but the chief 
seat of the production of leucocytes, as of red cells, is found in the 
embryonal liver. In both situations the wandering cells are found 
in the lymph and blood capillaries, in the interstices of the connective 
tissues, and between the liver cells. In later embryonal life the forma- 
tion of leucocytes is gradually transferred from the liver to the 
lymphoid and adenoid tissues, as indicated by the development of 
the lymph nodes, spleen, marrow, and thymus. While the majority 
of observers believe that these tissues are at all times developed by 
the proliferation of extravascular wandering cells and leucoblasts, 
Stohr and Gulland believe that these cells multiply principally within 
the vesseh and subsequently wander out at certain localities, where 
they collect to form lymph nodes. 

Formation of Leucocytes in Adult Life. Under normal conditions 
the reproduction of leucocytes in the adult is limited to the lymphoid 
structures, including the lymph nodes, spleen, marrow, and hemo- 
lymph nodes. 

Hemolymph Nodes. Warthin has recently drawn attention to the consider- 
able importance of the hemolymph nodes in the development and destruction 
of red and white blood cells. The existence of these nodes has long been 
known, but until recently they have received only desultory notice from 
pathologists. 

Warthin divides the nodes into two types resembling the spleen and the 
marrow. Transitional forms occur, and the types appear to undergo cyclical 
changes with occasional reversion to the simple lymph node. The splenic 
type IS abundantly present in all animals in the retroperitoneal and thoracic 
regions, while the myeloid type is limited to the retroperitoneal region. The 
structure of the splenic type "is that of a small lymph node with blood sinuses, but 
without distinct Malpighian bodies. Drummond finds smooth muscle in nearly 
all cases and sometimes lymphoid sheaths about small arteries. He states that 
the characteristic feature is the large size of the sinuses and the presence of 
macrophages holding pigment and red cells. Warthin finds that in physio- 
logical states the hemolymph nodes are scanty and seem to play little part in 
blood formation, but in pathological conditions the nodes increase in size and 
number, new ones forming in lymph nodes and fat tissue, and they exhibit 



184 GENERAL PHYSIOLOGY AND PATHOLOGY. 

pronounced signs of red-cell destruction, although never forming red cells. 
In diseases of the blood they undergo changes homologous with those of the 
spleen and marrow. In pernicious anemia he finds the hemolymph nodes 
increased in size and number and exhibiting very marked signs of destruction 
of red cells, and points out that the enlargement of the lymph nodes reported 
in this disease by many observers is probably referable to this type of lesion, 

Appearance of Different Varieties of Leucocytes. In the later 
months of fetal life the blood begins to show the presence of other 
varieties of leucocytes besides the lymphocytes. The minute mor- 
phology of these early cells and the exact time of their appearance is 
not known, but it is certain that all varieties seen in the adult are 
present at birth, and there is much evidence to show that long before 
this period the development of several distinct types of leucocytes 
is well established and their formation at least partially limited to 
certain viscera. 

Sabrazes and Muratet examined the blood of a human fetus of the eleventh 
week of gestation. The proportion of red to white cells was 1 : 400. There 
were twelve times as many non-nucleated as nucleated red cells, and almost as 
many megaloblasts. The normoblasts were polychromatic, the megaloblasts and 
non-nucleated cells orthochromatic. The leucocytes were mostly medium- 
sized and large mononuclear cells. Polynuclear neutrophile cells were very 
scanty, and no eosinophile cells could be found. 

The Basophile Leucocytes. These cells are the direct descendants 
of the first embryonal leucocytes, and are undoubtedly produced, in 
the adult as in the embryo, by the mitotic division of cells lying in 
the proliferation zones of lymph follicles, and diffusely in all adenoid 
tissues. Virchovv' regarded the small basophile cells {lymphocytes) as 
originating in the lymph nodes and the large basophile cells {spleno- 
cytes) as derivativ^es of the spleen ; but this distinction has not been 
supported. It seems more probable, though by no meaus certain, 
that most or all of the larger basophilic leucocytes of normal blood 
are developed from lymphocytes. Kanthack and Hardy endeavored 
to subdivide this class into basophile and hyaline cells, the former 
being '' tissue cells '' and rarely appearing in the blood, the latter 
identical with the ordinary small and large lymphocytes. Kanthack's 
coarsely granular basophile cell is the ''mast-ceil,'^ which has no con- 
nection with the lymphocytes ; but his finely granular basophile cell 
has not been recognized as distinct froni the hyaline cells whose 
protoplasm is not strictly hyaline but reticulated, and which 
undoubtedly originates in the lymphoid organs. 

The mast-cells, which contain large, strongly basophilic granules, 
are classed by Kanthack as celomic (tissue) cells. They are quite 
different in appearance from the coarsely granular basophile cells of 
chronically inflamed tissues, and their exact origin has not been 
explained. (See " Mast-cells," Section on Leukemia.) 

The Neutrophile Leucocytes. The time of appearance of these cells 
in the human embryo is not known. Saxer finds in the sheep's 
embryo of 4.5 cm., in connective tissues and scantily in the lymph, 
polynuclear leucocytes identical in appearance with those of the 
adult animal. 



DEVELOPMENT OF BLOOD CELLS. 185 

If the poly nuclear leucocytes ai^e developed from lymphocytes, 
the seat of their production in the infant at birth is, of course, coex- 
tensive with that of lymphocytes ; but if poly nuclear neutrophil e 
cells are derived as a separate series from the neutrophile myelocytes, 
their formation is limited, at birth and thereafter, to the red marrow. 
Whichever view may be correct, it is certain that the neutrophile 
myelocytes are largely concerned in the formation of these cells, and 
that the marrow is the chief seat of their production. 

The opinion widely held that neutrophile leucocytes are developmental 
forms of the lymphocyte of the blood still lacks any definite support. That 
they are certainly produced by mitotic division of neutrophile myelocytes has, 
however, been placed beyond question by the constant appearance of increased 
numbers of mitotic myelocytes in leukemia and leucocytosis. The larger size, 
distinctly vesicular nucleus, basophilic protoplasm, and invariable absence of 
neutrophile granules in the most typical examples of the so-called " transi- 
tional leucocytes " cannot be reconciled with the view that these cells are ever 
transformed into neutrophile leucocytes. Some have referred to myelocytes 
deficient in neutrophile granules as transitional forms, but in leukemia where 
such cells are common, a deficiency of neutrophile granules is veiy frequent 
in both myelocytes and polynuclear leucocytes. Again, if basophile leuco- 
cytes form neutrophile cells it is difficult to see why numerous transition forms 
are not found in lymphatic leukemia where basophile cells are excessively 
numerous, but neutrophile are abnormally scarce. Lowit here resorts to the 
suggestion that the further development of these cells is inhibited by changes 
in the plasma. Yet in myelogenous leukemia no such changes in the plasma 
prevent the transformation of myelocytes into polynuclear leucocytes which 
here often outnumber the myelocytes. 

Out of the constantly accumulating evidence which goes to establish the 
specific qualities of different leucocytes may be mentioned the studies of 
Zenoni, who found no change in the proportion of neutrophile cells during 
very marked variations, experimentally induced, of the basophile. 

In health, Dominici finds that the polynuclear cells are developed exclu- 
sively in the marrow and from myelocytes. In the intestinal lymphoid tissue 
and omentum of typhoid infections he finds lymphocytes changing into mye- 
locytes, and in the lymph nodes on the third day of vaccinia in the rabbit he 
finds lymphocytes changing into polynuclear cells without the intermediate 
stage of the myelocyte. 

Bezancon in pneumonia, and Frankel and Japha in scarlet fever, and 
Dominici, describe an active formation of polynuclear cells in the spleen. 
The writer has seen in the spleen of pneumonia a great abundance of poly- 
nuclear leucocytes in the pulp cords of the organ, but only in cases of general 
pneumococcus septicemia, in which the condition may be regarded either as a 
transformation of the original mononuclear cells of the cords into polynuclear, or 
as an infiltration from the blood stream by polynuclear leucocytes. Such condi- 
tions do not seem to present favorable opportunities for the demonstration 
that polynuclear neutrophile cells may develop from the mononuclear baso- 
phile cells of the spleen. More suggestive of such a development is a speci- 
men of the spleen from a case of puerperal streptococcus septicemia, recently 
encountered by the writer, in which this organ is the seat of multiple miliary 
abscesses, in some of which all the cells are polynuclear, in others, nearly 
all are mononuclear, while numerous transitional stages are to be found. 

The Eosinophile Leucocytes. These cells very early become differ- 
entiated from the primary leucocytes, having been found in the 
chick^s blood on the fifth day of incubation (EngeP) and in the 
human thymus and lymph nodes before the appearance of bone 
marrow (Schaffer, Gulland). Though it was early found that they 
are specially abimdant in the marrow, their very wide distribution 



186 GEXERAL PHYSIOLOGY AXD PATHOLOGY. 

in the tissues shows that the conditions essential to their development 
are not limited to any single organ or tissue. The discovery of 
mitotic division of eosinophile leucocytes, first reported by Miiller 
and subsequently verified by many others, would seem sufficient 
proof that these cells constitute a distinct self-perpetuating series. 
Nevertheless, many current writers either tacitly accept or actively 
argue that the eosinophiles are derived from the neutrophile granules 
of polynuclear leucocytes. Demonstration of the truth of this view 
is at present entirely lacking. Only Gulland attempts to describe 
transitional stages between neutrophile and eosinophile granules in 
embryonal blood cells, but his claims have not only not been veri- 
fied, but are distinctly contradicted by the results of the vast majority 
of observers, who have failed to find any such transition forms in 
the adult. On the other hand, there is abundant phvsiological, mor- 
phological, and microchemical evidence to show that eosinophile 
leucocytes are not derived from neutrophile. 

Physiologically, the eosinophile cells are celomic tissue cells, finding 
their natural habitat in the tissues and not in the blood, whereas the 
neutrophile leucocytes are chiefly hemic cells occurring almost exclu- 
sively in the blood. Moreover, since these cells certainly multiply 
by mitosis, it is unnecessary and contrary to analogy to suppose that 
any other method of development or formation exists. The morpho- 
logical evidence includes the fact that transitional granules have not 
been demonstrated ; that the nuclei of the two cells have rather 
distinctive characters, and that the granules are integral parts of the 
cytoreticulum (Heidenhain, Gulland), and not, as has been supposed, 
excretory products in the cell. The microchemical evidence shows 
that the eosinophile granules yield Lilienfeld^s and Monties reaction 
for phosphorus (Sherrington), may contain iron (Barker, Arnold), 
and give the vanillin and aldehyde reactions of TTeiss, none of which 
characters have been demonstrated in neutrophile granules. 



THE BLOOD PLATES. 

The blood plates were first described by Donne, in 1842, who 
found them in blood upon the addition of water and regarded them 
as particles of globulin derived from the red cells. In 1847 Zim- 
merman found in defibrinated blood certain ^^ elementary granules,'^ 
at first about la in diameter, but gradually increasing in size, and, 
as he believed, eventually becoming red cells. 

The first complete descriptions were give by Schulze, Kolliker,- 
Eanvier, and Bizzozero,^ and later by many authors. 

They are circular or ovoid, colorless, homogeneons, or granular 
bodies, about 1 w to 3« in diameter, usually showing no nuclear por- 
tion, and staining lightly by both basic and acid dyes. The common 
impression that they disappear promptly after shedding is true only 
of the spindle cells of the blood of lower animals, while human blood 
plates are scanty in fresh blood and increase in number upon stand- 
ing. They are extremely cohesive and apparently of high gravity, 



DEVELOPMENT OF BLOOD CELLS. 187 

and since they collect in masses from which the fibrinous threads of 
coagulating blood commonly radiate, they are supposed to take an 
important part in the formation of fibrin. 

On account of their uncertain morphology and origin, attempts to 
enumerate these bodies have not been very successful. In normal 
blood they may be said to vary between 180,000 (Fusari) and 500,000 
(Pruss). Estimates of their numbers based upon the general appear- 
ance of the blood indicate that they are specially abundant in afebrile 
anemias, leukemia, hemorrhages, and that they are deficient in febrile 
diseases, malaria, and after the administration of various poisons 
(Afanissiew, Limbeck, Fusari, Pizzini). 

The significance of the so-called " third corpuscles " of human 
blood, the blood plates, appears to have been greatly obscured by the 
discovery in the blood of frogs by Recklinghausen, and of birds by 
Hayeni, and Bizzozero and Torre, of small spindle-shaped elements, 
which differ from red cells in the absence of hemoglobin and from 
leucocytes in their simple oval nucleus and non-ameboid protoplasm, 
and which have been regarded as the homologue of the human blood 
plates. Lowit^ classes these spindle cells with leucocytes. Miiller 
believes them to be peculiar elements without relation to either red 
or white cells. Ranvier regarded them as loosened vascular endo- 
thelia. The conclusion of Recklinghausen, Globulew, Schlarewsky, 
Bizzozero, Hayem, Yulpian, Eberth, and Schimmelbusch, that these 
cells are analogues of the blood plates, is the chief ground for the 
belief in the existence of a third corpuscle in human blood. 

When the evidence derived from the examination of human blood 
is considered, it becomes clear that the existence of a third cellulai^ 
body is without proof. Bizzozero's convincing demonstration of the 
presence of extremely fragile bodies in the blood of the frog's mesen- 
tery has naturally never been repeated in human blood, and the dis- 
similarity between human blood plates and the spindle cells of the 
frog requires much more cogent evidence of the relation of these two 
bodies than has yet been furnished. Consequently later investigators 
have with apparent success endeavored to show that the blood plates 
are not cells, but detritus of cells or of plasma. Howell, Gibson, and 
Hlava regard the blood plates as fragments of the nuclei of disin- 
tegrated leucocytes. Lowit believes many of them to be precipitated 
globulin particles, and others to be fragments of degenerating leuco- 
cytes. On account of their chemical composition Lilienfeld holds 
that they consist of nuclein, and that they are derived principally 
from the nuclei of disintegrated leucocytes. Czerrnak finds them 
abundantly in the proliferation zones of lymphoid organs, and, with 
Mondino and Sala, believes them to be fragments of the nuclei of 
colorless cells. 

The studies of Klebs, Engel, Bremer, Wlassow, Arnold,- Maxi- 
mow, and others, have placed beyond doubt the opinion that the 
chief source of blood plates is by the extrusion from red cells of 
masses or chains of globular material, which give many of the reac- 
tions of the nucleoproteids. While this process may be observed in 
almost every dry specimen stained by methylene blue (Plate IL, 



188 GENERAL PHYSIOL OGY AND PA THOL OGY. 

Fig. 2)^ it appears to be favored by proximity to leucocytes, raay be 
accelerated by many reagents, and is probably specially frequent in 
young red cells. 

A recent and one of the most exhaustive studies of batrachian spindle cells 
is that of Eisen. This observer concludes that the fusiform or spindle cell in 
Batrachoseps arises by extrusion of a part of the mitotic nucleus of the red 
cell together with some elements of the cytoplasm. This spindle cell is capa- 
ble of development and of division into two or more plasmocytes (blood plates). 
The plasmocyte is composed of archosome and three cytoplasmic zones, but 
has no nucleus. Yet Eisen claims that it is capable of growth by assimilation 
of food, exhibits phagocytosis and motility, and survives as an independent 
corpuscle in the blood stream. 

There is a somewhat distant analogy between the method of development 
of the plasmocytes, as described by Eisen, and of the blood plates as observed 
in human blood, as in both cases these elements represent extruded portions 
of red cells. It appears very unlikely that the process described in batrachians 
can be successfully demonstrated in man, while the criteria on which Eisen 
bases his claim that the plasmocytes are true cells will not satisfy the majority 
of histologists. At best these elements are only extruded fragments of cells, 
even in batrachians. 

Neither phagocytosis, nor increase in size, nor signs of motility will prove 
sufficient evidence of the cellular nature of these bodies. Nevertheless, while 
the majority of blood plates in man must be regarded as extrusions of material 
from red cells, the comparative study of these bodies suggests that it may be 
possible to distinguish among human blood plates some which have some 
other origin and a structure similar to those of batrachians. Recently Deetjen, 
examining fresh human blood on his salt-agar medium, has described blood 
plates which exhibited ameboid motion and a structure recalling that of the 
blood plates of batrachians. 

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His. Zeit. f. Wissensch. Zool., Bd. 10-11. 

Hlava. Arch. f. exper. Path. u. Pharni., Bd. 17. 

Howell. Jour, of Morph., 1891, vol. iv. p. 57. 

Israel, Pappenheim. Virchow's Archiv, 153. 

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Maurer. Morph. Jahrbuch., Bd. 16, p. 203. 

Masslow. Archiv f. micr. Anat., Bd. 51. 

Maximow. Archiv f. Anat. u. Physiol. Anat. Abtl., 1899, p. 33 

Mondino, Sola. Archiv. Ital. de Biol., XII. 

Muir, Drummond. Jour, of Anat. and Phj^siol., vol. xxviii. p. 125. 

Midler. Sitzungsber. d. kais. Acad. d. Wissen., Wien, 1889, Bd. 98 Deut. 
Archiv f. klin. Med., 1891, Bd. 48. 

Naegeli. Deut. med. Woch., 1900, p. 287. 

Neumann. ^ Zeit. f. klin. Med., Bd. 3. ^ Archiv f. micr. Anat., 1876, Bd. 12. 
2 Med. Centralblatt, 1868, Archiv f. micr. Anat., 1876, Bd, 12. Virchow's 
Archiv, 1890, Bd. 119, p. 386. 

Obrastzow. ^ Cent, f . d. med. Wissen., 1880, p. 433. ^ Virchow's Archiv, Bd. 84. 

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Schafer. Quain's Anat. Hist., 1891, p. 218. 

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Schulze. Arch. f. micr. Anat., Bd. 1, 1865. 

Sherrington. Proc. Royal Soc, 1894, vol. Iv. p. 161. 

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Spuler. Archiv f. micr."^Anat., Bd. 40. 

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Wissosky. Archiv f. micr. Anat., 1877, Bd. 13. 

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Zimmerman. Rust's Mag. f. d. gesam. Heilkunde, 1846, Bd. 66, H. 2. 



PART II. 

SPECIAL PATHOLOGY OF THE BLOOD. 



CHAPTER VI. 

< 

CHLOROSIS. 

Chlorosis is a primary anemia occurring almost exclusively in 
young women, rarely in young men, resulting from defective hemato- 
genesis and affecting principally the hemoglobin, but, secondarily, 
also, the number of red cells. 

Etiology. The studies of the etiology of chlorosis having estab- 
lished a great variety of predisposing and exciting causes, and ren- 
dered it evident that the disease results under very many diverse 
conditions, have left the essential factor in the evolution of the disease 
undetermined. On this account some are inclined to regard chlorosis 
as a symptomatic anemia, holding the peculiar clinical characters of 
the disease to result from the age and constitution of the individuals 
in whom it occurs (Kruger). 

Regarding the general causes, a number of theories, supported by 
many important facts, have been brought to light. 

Hypoplasia of the arterial system is an anatomical groundwork 
shown by Rokitansky and Virchow to exist in a certain group of 
cases. This hypoplasia may affect only the heart and larger arteries 
or the genital organs as well, or is frequently associated with the 
other developmental anomalies of the constitutio lymphatica. More 
recent studies (Paltauf, Ortner, Fraentzel) indicate that the congeni- 
tally small heart and aorta are more closely associated with the 
" constitutio lymphatica '' and with cardiac disease than with chlorosis. 
This hypoplasia has been found in subjects never suffering from 
chlorosis, and the majority of chlorotics give no other evidence of 
such vascular anomalies and make complete and permanent recovery. 

Intestinal autointoxication was first suggested as the essential cause 
of chlorosis by Hoffman, and this theory has been supported on 
various clinical and pathological grounds by Duclos, Clark, Noth- 
nagel, Bouchard, and many others. Bunge's authority has lent 
some force to the autotoxic theory, as this investigator holds that 
the blood obtains iron solely from the nucleo-albumins, the iron from 
which is combined with sulphur during intestinal putrefaction and 
thus becomes non-absorbable. In chlorosis the iron administered 



192 SPECIAL PATHOLOGY OF THE BLOOD. 

by mouth combines with the H2S and permits the normal absorption 
of the nucleo-albumins. 

This theory has been completely set aside by the demonstration 
by V. ^oorden/ Eethers, Morner, and Lipman and Wulf, that in 
chlorosis increased intestinal putrefaction is not commonly present, 
nor is there increased excretion of the derivatives of Hb. Stockman 
showed, moreover, that sulphate of iron will cure the disease, while 
bismuth and some otiier absorbents of HgS will not. Intestinal 
intoxication can, therefore, figure in only a limited group of cases. 

v. Hosslin, finding marked increase of iron in the feces of some 
chlorotic patients, concluded that the blood changes result from small 
multiple intestinal hemorrhages. Luton accepts this theory. 

Functional disturbances of the nervous system have from the first 
been actively maintained as prominent or exclusive etiological factors 
in chlorosis. The train of events here involved is variously explained. 
Murri supposes that there is a vasomotor disturbance arising from 
the generative organs, and causing changes first in the rate of flow, 
later in the chemistry of the blood. This theory represents the 
culmination of opinion as handed down by the older physicians 
(Trousseau, cf. Lloyd Jones). According to Meinert, the nervous 
influence arises from irritation of the abdominal sympathetic and 
results from gastroptosis. This observer has brought together very 
strong evidence to show that in one group of cases the above condition 
must be an important factor in the coincident anemia. Kruger 
believes that hypertrophy of the spleen commonly associated with 
chlorosis (Fuhrer, Scharlau, Chvostek, Clement, Grawitz, Eummo, 
and Dorri) is an indication of disturbance of function in this organ, 
which results in an increased destruction of Hb. This disturbance 
of function is believed to arise through irritation of the sympathetic, 
in the genital organs, stomach, intestines, etc. 

Grawitz believes that the disease is a vasomotor neurosis, with 
secondary changes in the blood consisting in an increase of plasma, 
which infiltrates the red cells and replaces the Hb. This condition 
is brought about by a disturbance in the interchange of fluids between 
the blood and the tissues leaving an excess of fluids in both. That 
the cells are at the same time deficient in Hb he explains as a result 
of the imbibition of fluids by their progenitors in the bone-marrow. 
To support this belief he emphasizes the nervous phenomena of the 
disease, refers to the fact that the symptoms are often out of propor- 
tion to the changes in the blood, which when severe he attributes 
to complications. He regards the initial loss of weight which many 
chlorotics suffer in the beginning of treatment as a sign of general 
reduction of body fluids. 

This theory is in accord with many results of recent study, espe- 
■cially those which indicate that a normal amount of iron is main- 
tained in most cases, and that an excess of plasma is one of the 
essential features of the disease. It appears, however, to give in- 
adequate importance to the loss of Hb, to the changes in the blood 
of severer cases, and to the therapeutic effects of irritant preparations 
of iron. 



CHLOROSIS. 193 

Predisposing Causes. The almost exclusive occurrence of the dis- 
ease near the establishment of menstruation must prove any theory 
of etiology inadequate which fails to consider the age of puberty, the 
female sex, and the function of menstruation. There is abundant 
evidence to show that heredity also is an important factor^ as the 
disease is often observed in the daughters of chlorotic mothers, while 
a tuberculous family history has been remarkably frequent in some 
series of cases (Trousseau, Jolly, Bramwell). 

Great importance undoubtedly attaches to general lack of hygiene, 
especially to the combination of poor food and mental depression. 
Stockman's analyses indicate that the diet of chlorotic girls contains, 
as a rule, too little iron. 

Considering the evidence thus briefly reviewed, the writer con- 
cludes that chlorosis is a specific form of essential anemia which 
results from the association of several factors, of which the two most 
important and invariably present are (1) a predisposition to the dis- 
ease, and (2) defective absorption of iron from the food. 

The predisposing factors are most pronounced in young girls at 
the establishment of menstruation, when the unaccustomed losses of 
blood and the peculiar changes in the nervous system favor the 
expression of hereditary tendencies and exaggerate the effects of bad 
hygiene ; and when additional elements are thrown in the balance, 
such as improper food, constipation, gastroptosis, mental depression, 
etc., the blood begins to suffer in a peculiar way, and clinical symp- 
toms are established which are not seen in secondary anemias occur- 
ring in the same subjects. The essential importance of the absorption 
of iron is indicated by its specific action, but it seems unnecessary to 
conclude, as Stockman has done, that the food must be deficient in 
iron, provided digestion and absorption are defective. It seems to be 
an invariable rule that chlorotics do not recover until the appetite 
improves. 

The exact nature of the pathogenic process in the disease remains, 
however, untouched by these considerations, and it still remains 
undetermined just how and where the elaboration of Hb is disturbed, 
whether in the intestinal mucosa (Garrod, Forchheimer), or in the 
spleen (Kruger), or in the bone-marrow. At present the weight of 
evidence appears to be almost conclusive that chlorosis results from 
a functional insufficiency of the bone-marrow, brought about in con- 
genitally predisposed subjects by a series of conditions most often 
combined in young women at puberty. 

Changes in the Blood. Specific Gravity. The specific gravity 
of the blood in chlorosis is reduced in very uniform ratio with the 
loss in Hb. From the observations of Devoto, Hammarschlag, 
Schmaltz, Siegel, Hock and Schlesinger, Menicanti, Stintzing, and 
Biernacki, it has been shown that this constant relation between 
specific gravity and Hb-content is somewhat peculiar to chlorosis. It is 
most uniform when there is no great reduction in cells, but in the 
severer types of the disease the ratio is less constant. 

Jones found the specific gravity of the blood between 1.032 and 
1.045 in eighty-seven cases, while that of the serum remained nearly 

13 



194 SPECIAL PATHOLOGY OF THE BLOOD, 

normal, 1.0259 to 1.029. These results were verified by Ham- 
marschlag in thirty cases, in which the blood averaged 1.045, the 
serum 1.030. The reduction in gravity of chlorosis corresponds, 
according to Jones, to a physiological diminution occurring in girls 
at puberty, but not in boys. Grawitz places the specific gravity at 
the height of the disease between the limits 1.035 and 1.045, and 
states that below 1.035 some complication is indicated. 

The bulk of blood is probably not altered in uncomplicated chlo- 
rosis, although Lloyd Jones considers an increase in the volume of 
plasma to be a very constant feature, and Stintzing and Gumprecht 
believe that oligemia exists in some peculiar cases. The exuded drop 
is pale in proportion to the anemia, and abnormally fluid. 

By the carbonic oxide method Smith calculated that the blood in 
chlorosis is much increased in volume, finding that while the total 
oxygen capacity is normal, the percentage capacity for the unit of 
blood is reduced fully 50 per cent. These results would indicate 
that the volume of blood is nearly doubled, and they cannot be 
accepted without confirmation. 

The Hemoglobin. The chief alteration in the blood is the loss of 
Hb, which is so far out of proportion to the reduction in red cells 
that a low Hb-index is one of the diagnostic features of the disease. 

A contrary opinion is held by Eichhorst and Zumpf, and espe- 
cially by Biernacki, who, finding a normal or increased percentage 
of iron in the dried residue of the blood in some cases, believe 
that a loss of other albumins and not especially of Hb is the essential 
change in the disease. The basis of this dissenting opinion will be 
further considered later. 

The percentage of Hb obtained by modern instruments has been 
reported as low as 10 (Bramwell) ; but when the Hb falls below 20 
per cent, there should always be a suspicion of some complicated or 
secondary anemia. 

In cases of average severity the Hb ranges between 35 and 45 per 
cent., and the Hb-index about 0.5 ; yet some authors record severe 
cases with high Hb-index (0.80 to 0.95, Bramwell), although from 
the details of these reports it is not clear to what this variation from 
the rule is referable. These cases, in the writer's experience, fall 
in an intermediate group between chlorosis and pernicious anemia, 
and are more refractory than the others. Occasionally the Hb-index 
is very low (0.20, Bramwell). 

V. Noorden,^ from extensive observations, finds that the Hb-index 
is apt to be somewhat higher in recurrent than in initial attacks, but 
Romberg could not verify this statement in a group of relapsing 
cases. The writer has seen illustrations of v. Noorden's rule, and, 
since increase in size of cells is an indication of chronicity in anemia, 
believes that the observation is, in general, well founded ; yet, as 
Romberg states, the character of the blood changes is controlled by 
individual peculiarities in blood formation and by numerous unhy- 
gienic conditions. 

The red cells are in most cases slightly reduced, although almost 
invariably much less affected than the Hb ; yet not infrequently a 



PLATE IV. 








Mild Chlorosis. (Eosin and Methylene Blue.) 



Fig. 1, Slightly deformed red cells, with enlarged central clear areas, indicating loss of Hb. 

Fig. 2. Poikilocyte. 

Figs. 3. Normal rouleaux. 

Fig. 4. Medium-sized lymphocyte. 

Fig. 5. Polynuclear neutrophile leucocyte. 



CHLOROSIS. 195 

considerable grade of anemia is associated with a normal proportion 
of red cells. A high count of red cells is a favorable prognostic sign. 

In cases of average severity the red cells run from 3,500,000 to 
4,000,000, while in severe cases the number falls below 3,000,000. 
Exceptional examples in which less than 2,000,000 cells were found 
are recorded by Bramweil, Cabot, and many others, while Limbeck 
records one case with 1,190,000, and Hayem a minimum of 937,360. 
In such cases the Hb-index is often comparatively high. 

Grawitz emphasizes the importance of the diminution in the 
volume of the red cells, which he finds without exception is very 
marked, their volume averaging 20 per cent, instead of the normal 
40 to 50 per cent. Since the cells are of normal number and normal 
size, he refers the diminution of bulk to infiltration with serum 
which is lost in the process of centrifuging. 

In morphology the red cells present characteristic changes. In 
mild cases and those of average severity the sole alteration is a loss 
of Hb, which causes a progressive widening of the central clear area 
to be observed in cells rather thickly spread and slowly dried. In 
all well-marked cases the appearance of such blood in stained smears 
is characteristic of simple anemia. It is always possible, however, 
to find a few very small cells and some extremely deficient in Hb, 
but in the less severe cases these features are not pronounced. (Plate 
IV.) 

When chlorosis is of long standing or of very severe grade, with 
hydremic plasma, and showing a tendency to relapse, the red cells 
begin to exhibit marked variations in size and to some extent also 
in shape. In most cases in which the response to iron is fairly 
prompt these changes do not affect any considerable proportion of 
cells. In others in which the response to iron is less certain there 
is a moderate number of large cells with abundant Hb. (Plate Y.) 

In no case do these changes reach the grade seen in pernicious 
anemia ; but in a group of cases which do not respond well to iron 
and are apt to relapse, the variations in size of the cells is consider- 
able, and many show an abundance of Hb. On the other hand, the 
writer has seen persistently relapsing chlorosis in which all the cells, 
varying considerably in size, were very deficient in Hb. 

Poikilocytosis may be seen in all severe cases of chlorosis, but is 
seldom very marked. 

Other changes occurring with moderate frequency in the red cells 
of chlorosis are the polychromatic degeneration of Maragliano and 
that of Gabritschewsky. Granular degeneration is seen to a slight 
extent in well-marked cases. It was observed by Stengel, White, 
and Pepper in eleven of eighteen cases. 

A qualitative change in the Hb in chlorosis is suggested by the 
results of Henrique's experiments, by which he finds that oxyhemo- 
globin is much more slowly reduced in chlorosis than in health or 
in other forms of anemia. 

Nucleated red cells are seen in the severer cases of chlorosis under 
various conditions. It is said that when present they are subject to 
periodical variations constituting the "blood crises" (Xeudorfer) 



196 SPECIAL PATHOLOGY OF THE BLOOD. 

Most writers have found them too scanty even in severe cases to 
permit a fall verification that '' blood crises ^^ are of frequent occur- 
rence, and this common experience is in accord with the theory that 
functional insufficiency of the marrow is essentially connected with 
the pathogenesis of the disease. Their appearance is somewhat 
favored by rest in bed and large doses of iron, Avhich, as Hoffman 
has shown, induce hyperemia and cellular hyperplasia of the red 
marrow. The writer has seen an increased number during the leuco- 
cytosis of an intercurrent pneumonia. 

The nucleated red cells of chlorosis are of the normoblastic type, 
and while Neudorfer and Hammarschlag report finding megaloblasts 
in severe relapsing cases, the exact nature of these cases is not 
entirely clear. Their observations require confirmation. 

Chemistry. The alkalinity of chlorotic blood has been found 
by the majority of investigators to vary within normal limits (Kraus, 
Steindler, Limbeck) or in some cases to be slightly increased (Grae- 
ber, Peiper, Rumpf). v. Jaksch, hoAvever, found it diminished. 
Burmin, using Landois' method, which gave a normal alkalescence 
of 0.182 to 0.218 gramme of NaOH, found the alkalescence of 
chlorotic blood to ransre between 0.128 and 0.200 gramme ^aOH. 
The alkalescence varied with the red cells, and in six of nine cases 
the increase of these cells following the use of iron Avas accompanied 
by a corresponding increase in alkalescence. 

The ISOTONIC TENSION of the red cells Avas found by Limbeck in 
two cases to be very low (0.38 to 0.4 per cent. NaCl), their resist- 
ance, therefore, being correspondingly increased. Aporti tested the 
red cells in chlorosis by Viola's method, AAdiich determines the least, 
the medium, and the greatest resistance. The least resistance AA^as 
much below normal — /. e., some cells dissoh^ed very readily, but not 
more so than in secondary anemia. Iron at first rendered some 
cells even less resistant, but after some use the point of least resist- 
ance rose rapidly. 

The COAGULABILITY of chlorotic blood is notably greater than 
that of other forms of anemia of equal grade — a rule which accords 
Avith the fact of the preservation of the albumins of the plasma 
(cf. Biernacki). 

The PROPORTION OF AA^ATER in chlorotic blood increases from the 
normal (77 per cent.) to 80 to 90 per cent., and the dry residue falls 
from 22 or 36 per cent, to 19 per cent. Avith 60 to 70 j^er cent. Hb, 
or as low as 10.64 per cent, of residue with 25 per cent. Hb. In 
this residue the chlorides, as in all hydremic states, are in most cases 
considerably increased. Phosphorus is moderately reduced, and iron 
is deficient in the Avell-marked cases only (Biernacki). When the Hb 
is beloAv 70 per cent, the reduction in iron is rather uniformly pro- 
portionate Avith the loss in Hb. 

Albumins. Since the specific gravity of the serum is but slightly 
altered in the average case of chlorosis, the loss of substance must 
affect principally the red cells. It is very generally agreed that, 
as shown by Becquerel and Podier, the principle chiefly affected is 
the Hb ; but Biernacki found a normal proportion of iron in the dry 



CHLOBOSIS. 197 

residue of some milder cases of chlorosis, and has concluded that 
other albuminous constituents may suffer more than the Hb. In 
Biernacki's analyses of more severe cases, however, a marked and 
nniform reduction of iron is recorded. 

In all the severer cases the serum is poor in albumins, but 
markedly so only in very severe cases. The hydremia of the serum 
in chlorosis is relatively far less than in simple anemia, e.g., post- 
hemorrhagic (Grawitz). This rule is found by Stintzing and Gum- 
precht to hold only when the Hb is between 50 and 80 per cent., as 
illustrated in the following table : 





Hb. 21-30 


31-40 


41-50 


51-60 


61-70 


71-80 


81-85 


Dry 


r Simple Per cent. 


Per cent. 


Per cent. 


Per cent. 


Per cent. 


Per cent. 


Per cent. 


. j anemia. 13.4 


12.0 


13.3 


14.5 


16.1 


18.5 






[chlorosis. 


12.5 


13.4 


15.8 


18.3 


18.8 


19.0 



Regeneration of the Blood in Chlorosis. Red Cells and Hb. 
Hay em divided the process of regeneration of the blood in chlorosis 
into two periods : one in which the red cells are increased in number 
by the appearance of many small pale and deformed cells, followed 
by a second in which these new cells gradually acquire normal 
characters. Similar observations have been made by the majority 
of recent observers, who have regarded the small cells seen in relative 
excess in well-marked cases as being recently formed. On the other 
hand, Laache, Stintzing and Gumprecht, Reinert, and Graeber find 
that the increase in Hb usually outstrips that of the red cells. 

More recent studies in this field have thrown some light on the 
difficulty, Romberg showing that with a slight decrease of cells the 
Hb increases the more rapidly, while in cases with marked decrease 
in cells these increase first and more rapidly but less uniformly than 
the Hb. In some severe cases Romberg noted a slight initial diminu- 
tion in cells following the use of iron. 

Grawitz finds that the first change observed in the blood of severe 
cases is an increase in specific gravity (1.035 to 1.042) with simul- 
taneous increase in the number of red cells — -changes which he refers 
exclusively to diminution in the volume of plasma. Later the new 
formation of cells and the restoration of the Hb begin, and both 
progress usually with equal rapidity. 

Schaumann and Willebrand have recently fully demonstrated that 
in moderately severe cases, under iron, there is a progressive increase 
in the average diameter of the red cells, resulting from the disap- 
pearance of undersized corpuscles, while the number of large cells 
becomes considerable. The authors feel justified in concluding that 
the progress of regeneration is not marked by the appearance of many 
small pale cells, which they believe are degenerated forms. In 
Romberg's one hundred cases, in all of which the cells were below 
4,000,000, the average duration of treatment was 26.5 days, the Hb 
increasing 9.9 per cent, and the red cells 430,645 every ten days. 
The best results followed the use of ferri. carb. sac, but they did 
not use Bland's pills. 

Distinct polycythemia has in many instances been found to follow re- 
covery from chlorosis. Schaumann and Willebrand report 7,400,000 



198 SPECIAL PATHOLOGY OF THE BLOOD. 

cells, with 67 per cent. Hb, but found that the polycythemia usually 
diminishes as the Hb reaches a normal proportion. In some severe 
cases, on the other hand, it seems to be difficult to secure complete 
regeneration of the blood, and the anemia relapses. 

An increase (twelve pounds) in the patient's weight without corre- 
sponding increase in the Hb of the blood cells, but with increase in 
the solids of the sernm, has been reported by Grawitz as an interest- 
ing feature of the regeneration of the blood in chlorosis. A moderate 
increase in the number of nucleated red cells and of leucocytes is 
sometimes observed in cases rapidly recovering. 

Leucocytes. The leucocytes in the average case of chlorosis show 
no abnormal variation in numbers or proportions (Graeber, Grawitz). 
The average in 239 cases reported by Thayer, Cabot, and Romberg 
was 8013. Romberg's tables show a progressive diminution of leuco- 
cytes as the anemia grows more severe, and he refers this rule not 
to any absolute decrease in the number of cells, but to increase in 
the volume of plasma. 

Neusser, and Strauss and Rohnstein, hold that some less favorable 
types of chlorosis, without regard to their severity, show an excess of 
lymphocytes, while in others the presence of eosinophile cells indicates 
a more favorable type of the disease. In the latter group of cases 
Neusser's pupils found, during treatment with iron, a slight mixed 
leucocytosis in which the proportions of various cells were normal. 
In cases with lymphocytosis Da Costa found often 45 per cent., and 
as high as 67 per cent., of lymphocytes, among which the large 
lymphocytes were very abundant and frequently reached 20 to 30 
per cent., and as high as 40 per cent., of all the leucocytes present. 
In a few^ cases distinct leucocytosis has been reported, but was prob- 
ably referable to some obscure complication. 

The occurrence of myelocytes, as reported by Hammarschlag and 
l^eudorfer, is very unusual. 

Gilbert and Weil describe certain changes in the leucocytes which 
must be regarded as degenerative, including irregularities in the 
number and grouping of the neutrophile granules, subdivision of the 
nuclear lobes of the polynuclear cells, and some alterations in the 
mononuclear cells. 

Varieties of Chlorosis, (a) The typical examples of the disease 
observed in young women form a central group of cases which has 
furnished the classical and accepted picture of chlorosis. The blood 
in these cases shows a low Hb-index, with or without marked loss 
of cells. They run an acute or chronic course, but respond well to 
iron. On chemical analysis the dry residue and the iron are much 
diminished, and the symptoms are in proportion to the grade of 
anemia. 

Of these cases one may distinguish three groups of somewhat 
different prognosis : 

1. The red cells are slightly or not at all reduced (about 4,000,000) ; 
the Hb-index is low ; there are no changes in the size and shape of 
the cells. Such patients commonly recover very promptly, and the 
anemia does not relapse. 



PLATE V. 




Severe Chlorosis. ( Eosin and Methylene Blue. ) 



Fig. 1. Short rouleau of cells very deficient in Hb. 

Fig. 2. Medium-sized megalocyte deficient in Hb. 

Fig. 3. Microcystes deficient in Hb. 

Fig. 4. Large red cell with central droplet of Hb. 

Fig. 5. Red cell with central basophilic nuclear remnant. (Folychromasia of Maragliano.) 

Fig. 6. Norm.oblast. 

Fig. 7. PoljTtiuclear neutrophile leucocyte, over-stained with methylene blue and showing 

basophilic c\'i:oreticulum. 

Fig. 8. Blood plates. 



CHLOROSIS. 199 

2. The red cells are below 4,000,000, but there are no marked 
changes in the shape and size o£ the cells ; the Hb-index is very low ; 
the patients are prostrated, but with iron usually recover promptly, 
and the anemia does not often relapse. 

3. The red cells are markedly reduced (below 3,000,000 to 
3,500,000) ; there are considerable changes in shape and size, the 
Hb-index varies, but is usually very low ; the patient responds more 
slowly to iron, and the anemia often relapses. 

(b) A group of cases of idiopathic anemia common in young women 
has long been recognized, in which the symptoms resemble those of 
refractory chlorosis, but whicli in some other respects are quite dif- 
ferent. Delaiield states that they are chiefly distinguished by their 
failure to react to iron. A chronic course with relapses is commonly 
observed, but a change to distinct pernicious anemia rarely occurs. 
The blood of such subjects shows a marked reduction in red cells, 
commonly between 2,000,000 and 3,000,000, and marked variation 
in size of the cells, a considerable number of which have increased 
Hb. The Hb-index may be very low, but is apt to be higher than 
in the average case of chlorosis. The lymphocytes are commonly 
in excess. 

It is possible that some of these cases are much more anemic 
than the ordinary blood examination indicates, because complicated 
by oligoplasmia, as suggested by Lloyd Jones and Biernacki. 

(c) Pseudochlorosis is a term employed by various recent writers 
to denote a group of cases in which the external symptoms of 
chlorosis are present, but in which, from the examination of the 
blood, it is found that the Hb, number of red cells, percentage of 
dry residue, and usually the proportion of iron are nearly normal. 
Several explanations have been offered regarding these obscure cases. 

Lloyd Jones believes that they are cases of anemia with oligo- 
plasmia, in which the real deficiency of Hb and cells is masked by 
diminution in the quantity of plasma. He offers no chemical analyses 
to support his view. Biernacki has studied this condition in detail, 
and as a result of clinical observations and chemical analyses he 
concludes that in cases of anemia there is a condition of oligoplasmia 
wth hydremia of both cells and plasma, so that while the blood shows 
normal Hb, yet the swollen cells are deficient in this principle, and 
both cells and plasma are deficient in albumins. In short, Biernacl-i 
claims to have demonstrated that it is possible to have hydremic blood 
which yet gives a normal percentage of Hb and, a normal number of 
red^cells. Biernacki points out that two of the eight original cases 
examined by Becquerel and Rodier, and two cases reported by 
Stintzing and Gumprecht, showed slight hydremia, a nearly normal 
percentage of iron, but well-marked symptoms of chlorosis. He pro- 
tests against calling such cases pseudochlorosis, believing that they 
are genuine examples of the disease, and claims that the essential 
element in chlorosis is not the loss of Hb and iron, but that the 
disease is a neurosis with hydremia, and loith or without loss of iron. 

If Biernacki's results obtain confirmation, which they have not 
yet secured, much needed light may be thrown upon a large group 



200 SPECIAL PATHOLOGY OF THE BLOOD. 

of cases in which the symptoms of anemia are associated with appar- 
ently normal blood. Such cases occur usually in young women, are 
often encountered in gynecological clinics because of amenorrhea, 
and have been fully described, especially by Biernacki and Romberg. 
It is possible, also, that a similar explanation may apply to the cases 
of pseudochlorosis described by Stintzing and Gumprecht and others, 
and very commonly encountered in tuberculous subjects. 

Bibliography. 
Chlorosis. 

Aporti. Settimana med., 1899, No. 35. 

Biernacki. Zeit. f. klin. Med., Bd. 24, p. 500. 

Bihler. Deut. Archiv klin. Med., Bd. 52, p. 281. 

Bouchard. Lecons sur T autointoxication, Paris, 1887. 

Bramwell. Anemia, etc., p. 22. 

Bunge. Verh. XIII. Cong. inn. Med., 1895. 

Burmin. Zeit. f. kl. med., Bd. 39, p. 365. 

Chvostek. Wien. klin. Woch., 1893, p. 487. 

Clark. Lancet, 1887, II., p. 1003. 

Clement. Lyon Med., 1894, T. 75, p. 179. 

Devoto. Zeit. f. Heilk., Bd. 9. 

Duclos. Rev. gen. d. clin. et ther., 1887, p. 561 

Duncan Sitzungsber. d. Wien. Acad., 1867. 

Eichhorst. Cited by v. Noorden. 

Euren. Schmidt's Jahrbucher, Bd. 240, p. 213. 

Forchheimer. Amer- Jour. Med. Sci., vol. cvi. p. 8. 

Fraentzel. Zeit. f. klin. Med., Bd. 2, p. 217. 

Fuhrer. Archiv f. Heilk., 1856, p. 67. 

Garrod. Archiv, of Path, and Bact., 1892, a^oI. i. p. 195. 

Gilbert, Weil. Compt. Rend. Soc. Biol., 1899, p. 73. 

Graeber. Therapeut. Monatshefte, 1887, p. 380. Arb. a. d. med. -klin. Institut 
Miinchen, Leipzig, 1890. 

Gram. Fort. d. Med., 1884, p. 33. 

Grawitz. Klin. Pathol., p. 76. 

Hammarschlag. Zeit, f. klin. Med., Bd. 21, p. 475. Wien. med. Presse, 1894, 
p. 1068. 

Hayem. Du sang., p. 619. 

Hock, Schlesinger. Beitrage zur Kinderheilk., II., N. F., 1892. 

Hoffman. Lehrb. d. Constitutionskrank., 1893. Miinch. med. Woch,, 1899, 
p. 949. 

V. Hosslin. Miinch, med. Woch., 1890, p. 248. 

V. Jaksch. Prager med. Woch., 1890, No. 31. 

Jolly. Influence d. tuberc. sur Chlorose, Paris, 1890. 

Jones. Chlorosis, London, 1897, p. 23. 

Kraus. Zeit. f. Heilk., Bd. 10. 

Kruger. St. Petersburg med. Woch., 1892, p. 471. 

Laache. Die Anaemic, 1883, p. 81. Cited in Hoffman's Lehrbuch d. Consti- 
tutionskrank., Stuttgart, 1893. 

Lipman, Wulf. Leber Eiweisszersetzung bei Chlorose, Berlin, 1892. Cited by 
V. Noorden. 

Lichtenstern. Untersuch. u. d. Hemoglobingehalt d. Blut., 1878. 

Limbeck. Grundriss, etc., p. 305. 

Luton Bull. Soc. med. Rheims, No. 10. 

Meinert. Samml. klin. Vortrage, 1895. 

Menicanti. Deut. Archiv klin. Med., Bd. 50, p. 407. 

Morner. Zeit. f. physiol. Chem., 1893, XXIII. 

Murri. Semaine Med., 1894, p. 162. 

Neudorfer. Wien. med. Presse, 1894, p. 1068. 

V. Noorden. ^ Chlorose Wien., 1897. ^ Berl klin. Woch., 1895, p. 181. ^ Ibid., 
1894, p. 786. 

Nothnagel. Wien. med. Presse, 1891, No, 51. 

Ortner. Wien. klin. Woch., 1891, p. 2, 



CHLOBOSIS. 201 

Paltauf. Wien. klin. Woch., 1889, p. 877; 1890, p. 172. 
Peiper. Cent. f. inn. Med., 1891, No. 12. 
Pick. Wien. klin. Woch., 1891, p. 939. 
Rethers. Diss. Berlin, 1891. 
Romberg. Berl. klin. Woch., 1897, p. 533. 
Rumpf. Cent. f. klin. Med., 1891, p. 441. 
Rummo, Dori. Rif. Med., 1893, H. III. 

Scharlau. Theoretisch. Prakt. Abhand., Stettin, 1854, No. 3. Cited by v. 
Noorden, Nothnagel, VIII., 2, p. 87. 

Schaumann, Willebrand. Berl. klin. Woch., 1899, p. 9. 

Schmaltz. Deut. Archiv klin. Med., Bd. 47, p. 145. 

Siegel. Wien. klin. Woch., 1891, p. 606. 

Smith. Jour, of Physiol., vol. xxv. p. 6. 

Steindler. Cent. f. inn. Med., 1895, No. 27. 

Stengel, White, Pepper. Am. Jour. Med. Sci., vol. cxxiii. p. 873. 

Stintzing. XII. Cong. f. inn. Med. 

Stintzing, Gumprecht. Deut. Archiv klin. Med., Bd. 53, p. 287. 

Stockman. Brit. Med. Jour., 1893, vol. i. p. 880; 1895, vol. ii. p. 1473. 

Suhbotin. Zeit. f. Biol., 1871, Bd. 7. 

Zumpf. Inaug. Diss. Dorpat, 1891. 



CHAPTER VII. 

PROGRESSIVE PERNICIOUS ANEMIA. 

This term is applied to a peculiar disease of the blood resulting 
from defective hematogenesis and excessive hematolysis, characterized 
by severe and usually fatal anemia, peculiar morphological changes 
in the red cells, and by characteristic changes in the bone-marrow. 
Although excited by a number of well-recognized conditions, pro- 
gressive pernicious anemia differs from secondary anemia in the 
peculiar changes in the red cells, in the lesions of the marrow, in its 
tendency when once established to progress to a fatal issue, and in 
the fact that the anemia is apparently out of proportion to the exciting 
cause, while very often no cause whatever can be assigned. 

The disease has often been described as primary pernicious anemia, 
but since typical examples have been positively traced to the effects 
of intestinal parasites it becomes necessary to admit that this condi- 
tion of the blood is not always of cryptogenic origin. Nevertheless, 
its pathological features remain so distinctive as to justify the common 
belief in the peculiar nature of the disease. 

Historical. A review of the early literature on pernicious anemia, 
as collected by Eichhorst, Musser, and Stockman, shows that while 
the disease had previously been described by observers in many 
countries, its symptomatology, gross pathology, and separation from 
chlorosis and secondary anemia were not clearly stated until Addi- 
son in 1855 published the description of cases observed by him clini- 
cally and examined at autopsy during the previous decade. 

Of the earlier reported cases those of Andral (1821) in France, of 
Coombe (1823) and Hall (1843) in England, and of Channing (1849) 
in America were so clearly described as to leave no doubt that fatal 
idiopathic anemia was fully recognized by some observers at that early 
time. Channing and other Boston physicians had notes on such 
cases as early as 1832, and his descriptions of cases in 1849 were 
sufficiently complete to warrant their acceptance as referring to 
genuine examples of the disease. 

Lebert in Zurich had apparently recognized and partially described 
the disease as early as 1854 ; but his pathological reports were too 
scanty to demonstrate the probable specific nature of the malady, 
which he did not claim until 1858, although recognizing it as a fatal 
form of anemia. Long before this, as shown by Lepine, some promi- 
nent text-books had called attention to the occurrence of fatal cases 
of anemia, considering them usually as instances of fatal chlorosis 
(Piorry, Wunderlich, Schonlein, Rokitansky, Canstatt). 

Addison, however, offered more abundant clinical and pathological 
evidence to show that the disease is of idiopathic origin, fully dis- 



PBOGRESSIVE PERNICIOUS ANEMIA. 203 

tinguishable from secondary anemia ; but he supposed that the fatty 
changes were the cause, not the result, of the anemia. In 1857 Wilks^ 
description of seven cases was very clear, and indicates that the con- 
dition had then become well identified at Guy's Hospital and was 
distinguished from secondary anemia and, by the examination of the 
blood, from leukemia. 

In Germany there were fragmentary reports of probable cases by 
Zenker, 1856 ; Wagner, 1859 ; and Grohe, 1861 ; until Biermer in 
1868 collected a series of cases observed in Zurich during previous 
years, and gave such a systematic description of the clinical symptoms 
as to attract general attention to the malady as a special form of 
anemia. Biermer failed to add to the knowledge of the pathology 
of the disease and paid little attention to the blood ; and when 
Immerman contributed important critical studies, in 1874 to 1877, 
interest in the microscopic examination of the blood concerned 
chiefly the proportion of leucocytes. 

The early observers, especially Wilks, had noted the marked 
oligemia, hydremia, and feeble coagulation of the blood at autopsy, 
and by microscopic examination during life had demonstrated an 
excessive loss of red cells and a small proportion of leucocytes ; but 
for many years no further advance was attempted in this field. In 
1873 Ponfick found a relative increase of leucocytes in one case, 
probably from antemortem leucocytosis, and noted a greenish tinge 
of the serum. 

In 1876 Quincke described the appearance of microcytes and 
poikilocytes in several cases, while Eichhorst, at the same time, noted 
the absence of rouleaux and the increase of Hb in some microcytes, 
cells wdiich he regarded as pathognomonic of the disease. 

By this time Bizzozero's and Neumann's demonstration of the func- 
tion of the bone-marrow in blood formation began to turn attention 
to this tissue. Pepper (with Tyson) making the first contributions in 
a new field in 1875. Pepper found uncertain evidences of a cellular 
hyperplasia in some portions of the marrow, that of the radius 
appearing paler than normal, while that of the sternum was quite 
red. 

A great advance was made when Cohnheim in 1876 presented a 
brief communication on the changes in the bone-marrow in a case of 
pernicious anemia. He reported finding an unusual hyperplasia of 
the red marrow, with complete atrophy of fat cells, increase of myelo- 
cytes, large and small, absence of normal red cells, and the presence 
of megalocytes, microcytes, and large numbers of megaloblasts. In 
the blood of the vena cava he found a few large nucleated red cells, 
but had failed to find them in the peripheral blood during life. 
Cohnheim expressed the opinion that the essential element in the 
malady was a primary disease of the marrow affecting the develop- 
ment of the red corpuscles, leading to production of megalocytes at 
the expense of smaller properly functionating cells, the whole con- 
stituting a reversion to the embryonal ti/pe of blood formation. Cohn- 
heim thus completed the chain of pathological evidence that Avas 
required to establish the distinctive nature of the disease, and demon- 



204 SPECIAL PATHOLOGY OF THE BLOOD. 

strated the importance of closer study of the blood and marrow as 
the seat of the primary lesion. The further study of the marrow 
was taken up by Osier and Gardner, ^N^eumann, Litten and Orth, 
P. Grawitz/ and many others, whose results have shown that the 
study of the changes in the marrow gives the deepest insight iato 
the essential process of the disease. 

The first enumeration of red cells was reported by Sorensen, who, 
using Malassez's method, found in one case only 470,000 cells ; by 
Lepine,^ who, with Hayem's method, reported a reduction to 909,000 
and 378,750 ; and by Ferrand, who found 500,000 red cells and 10 
per cent, of Hb. Of morphological changes an increase in size of the 
red cells during the course of the disease was noted by Lepine ; a 
slight brownish tinge by Striker; the presence of ameboid processes 
by Scheby-Buch ; the oval form and absence of rouleaux by Bradbury. 
In 1876 Quincke described the appearance of microcytes and poikilo- 
cytes in several cases. Eichhorst (1878) found the most striking 
characteristics to be the large size, pallor, and scarcity of the red 
cells ; yet all these characteristics Eichhorst had seen in a case of 
gastric cancer, Avhence he maintained that the blood of pernicious 
anemia show^ed no single pathognomonic sign. While Quincke had 
observed that many microcytes seemed to contain an excess of Hb and 
that the blood of pernicious anemia was more highly colored than 
the number of red cells warranted, it was Hayem^ who first demon- 
strated that an increased Hb-index is characteristic of the disease, 
while Laache showed this feature to be referable to the presence of 
many megalocytes with increased Hb. 

By 1880 there were only two reported cases in which nucleated 
red cells had been found during life, when Ehrlich, examining 
stained dry preparations, claimed that while nucleated red cells were 
found in all cases of severe anemia, megaloblasts were seen exclu- 
sively in progressive pernicious anemia. Only in recent years has 
this claim been shown to be but partially valid. In 1891 Luzet first 
reported the discovery of mitotic nuclei in megaloblasts from the 
blood of a child, the occurrence of which has since been shown to be 
a nearly pathognomonic sign of the disease in adults. With the 
observations on polychromatic degenerative changes in red cells these 
lesions were found to be specially distinct in pernicious anemia. In 
one of V. Noorden's dissertations was first mentioned the occurrence 
of basic staining granules in the bodies of megalocytes, which was 
later verified by Askanazy and interpreted as evidence of karyorrhexis. 

The contributions on etiology Avhich have steadily accumulated 
from many sources, and the progress of the knowledge of the chem- 
istry of the blood, chiefly through the work of v. Jaksch, Grawitz, 
Dieballa, and others, will be considered under those topics. 

General Etiology. After the demonstration of striking and 
peculiar changes in the blood and marrow it was generally accepted 
that progressive pernicious anemia is of idiopathic origin, although 
Biermer enumerated a list of exciting causes which appeared to have 
been present in his cases, viz., insufficient food, bad hygiene, pro- 
longed diarrhea, repeated hemorrhages ; yet it appeared that the 



PBOGEESSIVE PERNICIOUS ANEMIA. 205 

assignable causes were inadequate to account for the result^ and it 
was felt that the disease could in no respect be classed with the 
ordinary cases of secondary anemia such as follow carcinoma, neph- 
ritis, hemorrhages, etc. 

The first retrenchment of this view was rendered necessary by the 
discover}^ of typical cases of the disease referable to the presence of 
intestinal parasites {hothriocephalus), and which recovered promptly 
after expulsion of the worms. These cases showed that there is not 
always a cryptogenic factor in the etiology of the disease, and 
that the presence of the typical blood changes does not necessarily 
imply a fatal course of the anemia. Likewise the changes in the 
marrow were for a time robbed of much of their pathognomonic 
value by the report that very similar changes are established in some 
cases of multiple hemorrhages (Neumann), tuberculosis (Litten), and 
gastric cancer (Eisenlohr). Further, the changes in the blood have 
now been shown to follow syphilis (F. Miiller),^ malaria^ (Bignami/^ 
the writer) ; atrophy of gastro-intestinal mucosa (Fenwick, Braba- 
zon, Henry, Osier, Nothnagel, Stengel) ; typhoid fever (Quincke, 
Rosenstein, P. Grawitz) ; prolonged diarrhea (Wilkes, Frankel, 
Strieker) ; myeloid sarcoma (Litten); in each of which conditions it 
is occasionally impossible to say that the cause is inadequate to the 
result, and there remain only the acute cases without demonstrable 
origin but referred by some to intestinal intoxication and the cases 
that follow pregnancy, which can still be held as of cryptogenic 
nature. 

Scope of the Term Progressive Pernicious Anemia. In view 
of this present state of the subject two plans of classification of the 
severe anemias of the Addison-Biermer type have been suggested by 
Birch-Hirschfeld and Grawitz. 

Birch-Hirschfeld claims that there is no good reason to separate on etio- 
logical grounds alone cases of severe anemia of cryptogenic origin from those 
like the anemia of hothriocephalus, in which an adequate cause is apparent, 
for both show the same anatomical evidence to prove that the pathological 
process in each is identical. He would, therefore, class together all severe 
anemic conditions, without regard to origin, in which there is degeneration 
and loss of red cells, increased destruction of tissue-albumins, and fatty 
changes in the viscera, and in which the chief factors are excessive destruction 
and defective formation of red cells. 

Against this proposition Grawitz urges that it is clinically inapplicable, 
because fatty changes in viscera can be recognized only after death ; that it 
classes together anemias arising from such diverse causes as cancer, malaria, 
sepsis, ankylostomiasis, etc., and that increased destruction of albumins is 
not a constant feature of the disease, although present in some forms of 
milder secondary anemia. Grawitz, therefore, proposes to throw out of the 
category of progressive pernicious anemia those cases in which the etiology is 
known, e. g., bothriocephalus, and to retain in this class only those cases in which 
the most thorough examination of the patient fails to show any primary disease. 

This suggestion accords with the view of those who fail to see in the histo- 
logical changes in blood and marrow evidence of a peculiar condition inter- 
preted by Cohnheim, Ehrlich, and many others, as a reversion to the embry- 
onal type of blood formation. 

The writer, having failed to find from any source a controversion 
of the view that the changes in the blood and marrow described in 



206 SPECIAL PATHOLOGY OF THE BLOOD. 

pernicious anemia result from a peculiar pathological process Avhich 
is essentially diiferent from that seen in the majority of secondary 
anemias, must accept the opinion that when the blood contains 
megaloblasts and a considerable proportion of megalocytes with 
increased Hb, while the lymphoid marrow shows marked hyperplasia 
of peculiar type, the condition should be called progressive pernicious 
anemia, without regard to its immediate exciting cause. The essen- 
tial process in the disease is a reversion of the marrow to a type of 
blood formation which in some respects resembles the embryonal ; 
and it would seem to make very little difference how various the 
exciting agents may be, whether syphilis, malaria, ankylostomiasis, 
or gastro-intestinal infection (Hunter), provided they all initiate the 
same process and stamp the anemia with certain self-perpetuating 
tendencies not seen in other conditions. 

Special Etiology. Progressive pernicious anemia is, as shown 
by its history, a disease of very general distribution and compara- 
tively frequent occurrence. In the Berlin City Hospital, Lazarus 
found 274 cases recorded in ten years, or 2 per cent, of the admis- 
sions. It is rather less common in New York hospitals, but con- 
sultants in the city see from six to twelve cases yearly. 

The female sex is considerably more subject to the disease than are 
males, owing probably to the predisposing influence of pregnancy 
(Miiller, Ehrlich). 

The 240 reported cases collected by Ehrlich were distributed 
between the ages as follows : 

Cases. Cases. 

ItolO 1 40 to 50 47 

10 to 20 22 50 to 60 33 

20 to 30 61 60 to 70 7 

30 to 40 67 70 to 80 2 

Monti and Berggrun collected sixteen cases in children, of which 
five occurred between the first and fifth years, and nine between the 
fifth and fourteenth years. Ehrlich hesitated to accept these as 
genuine cases on account of the uncertain significance of changes in 
the blood in early life. 

Intestinal Parasites. That the presence of intestinal parasites is 
frequently responsible for grave forms of progressive pernicious 
anemia was first demonstrated for ankylostoma duodenale by Gries- 
inger in 1854, and has since been amply attested. The work of 
Perroncito on ankylostoma was followed by the demonstration by 
Hoffmann, in 1885, that infection by bothriooephalus latus is much 
more frequently associated with very grave types of anemia indistin- 
guishable from the idiopathic progressive disease. 

Oxyuris was found associated with pernicious anemia first by 
Runeberg^ in 1887, and ascaris by Demme in two fatal cases in 
children. In all of these infections the grade of anemia may vary 
from the simple chlorotic type to the very rapid and fatal pernicious 
form. The presence of eosinophilia in any case of pernicious anemia, 
should suggest a search for one of these intestinal parasites. 



PROGRESSIVE PERNICIOUS ANEMIA, 207 

Repeated Hemorrhages. That genuiDe progressive pernicious 
anemia may follow repeated hemorrhages has been claimed by many 
observers who have not insisted upon Ehrlich's signs in their diag- 
noses (Habershon, Quincke, Scheperlen, Finney, Greenhow, Stock- 
man). In recent years reports of genuine cases of this origin have 
not been so numerous, yet Ehrlich and Lazarus accept as a fact 
their frequent occurrence from this cause. The writer has not seen 
any cases directly referable to hemorrhage. 

It is probable that the genuine cases observed after pregnancy are 
partly the result of the losses of blood during and after parturition. 
Stockman goes so far as to urge that all cases now called idiopathic 
are the result of repeated minute intestinal hemorrages, in which 
opinion he stands unsupported. 

While granting, as does Ehrlich, that the disease occasionally fol- 
lows repeated hemorrhages, it still remains true that the great 
majority of chronic posthemorrhagic anemias follow the type of 
secondary anemia with very low Hb-index, and with leucocytosis. 

Pregnancy was one of the conditions first recognized as a prominent 
exciting cause of pernicious anemia, the most numerous cases 
(twenty-nine, 35 per cent.) of those collected by Eichhorst (1878) 
coming under this heading. 

The genuineness of some of these cases may now be doubted, and 
at any rate the patients suffered from a variety of severe symptoms 
not at present regarded as belonging to the disease, so that Lazarus 
classes many of them as examples of secondary anemia and exhaus- 
tion. In others, however, the pregnancy was uneventful except for 
the spontaneous development of severe anemia ending fatally before 
or after parturition, so that Lebert ascribed to pregnancy a special 
nervous influence leading to fatal anemia, and Birch-Hirschfeld 
assumed that placental toxins affect first the plasma and later the 
red cells. These theoretical considerations have been rendered 
unnecessary by the gradual disappearance from the literature of cases 
of progressive anemia following pregnancy. Ehrlich could find only 
one case of this description in recent literature (Laache, Case 9). 
At Sloane Maternity Hospital from 1892 to 1899 the writer saw 
many cases of severe anemia, but none of the progressive pernicious 
type. Ahlfeld, in a wide experience, could not report a single case 
following pregnancy (1898). The rather numerous current reports 
of severe anemia following pregnancy refer to a severe secondary 
type, and, as Ehrlich concludes, it is impossible to ascribe to preg- 
nancy any peculiar influence in the origin of the disease. 

Syphilis. That syphilis is occasionally followed by anemia in 
which the morphological changes in the blood are identical with 
those of progressive pernicious anemia seems to be fairly well 
attested by the reported cases of Laache, Kjerner, and F. Miiller. 

In children suffering from hereditary syphilis the variations in 
the size of red cells, their increase of Hb, and the large numbers of 
megaloblasts seem to leave little doubt that, in this age at least, 
syphilis figures as an exciting cause of progressive pernicious anemia 
(Loos, Luzet) ; yet the reports in recent literature have not strength- 



208 SPECIAL PATHOLOGY OF THE BLOOD. 

ened the view that syphilis may lead directly to this peculiar type 
of anemia. The changes in the blood seen in the great majority of 
cases, although often severe, seem to follow the type of simple 
secondary anemia. Consequently Ehrlich and Lazarus doubt the 
existence of the disease as a result of syphilis. 

The writer has seen excess of deeply staining megalocytes and megalo- 
blasts in several cases of moderate severity shortly after florid syphilis, both 
in adults and infants, and has come to regard the diiferential diagnosis of 
severe secondary anemia in syphilitic subjects from progressive pernicious 
anemia as one of the most difficult fields in blood analysis. From experience 
at the autopsy-table it has been very apparent, however, that most cases show- 
ing advanced or active tertiary lesions have shown types of secondary 
anemia. The subject requires much more extensive clinical and pathological 
observation. 

Malaria. Although there are in the literature numerous cases of 
so-called pernicious anemia referred to malarial infection, the fact that 
the typical changes of the disease may be established as a result of 
chronic malaria was not demonstrated until Bignami and Dionisi 
reported their study of the marrow of fatal cases. Here were found 
the signs of megaloblastic hyperplasia in distinct form. Among the 
writer's Montauk cases there were no less than nineteen in which 
the blood showed a majority of megalocytes with increased Hb, and 
a considerable number of megaloblasts, and in one of these the 
lymphoid marrow was found markedly hyperplastic, with excess of 
megaloblasts, and an enormous number of young estivo-autumnal 
parasites. In all these cases the condition had become established 
within eight to ten weeks from the beginning of the infections, but 
the malarial element had doubtless been aided by exposure and poor 
food. 

The frequency of these cases among malarial subjects and the fact 
that the bone-marrow suffers in a peculiar way in many cases of 
estivo-autumnal infection are considerations which bear directly on 
the myelogenous origin of pernicious anemia. 

Typhoid Fever. Quincke and Rosenstein each report the trans- 
formation of the cachexia of typhoid fever into pernicious anemia, 
but in neither case do their reports show the presence of typical 
changes in the blood, both falling in the class of severe secondary 
anemia. 

G-astro-intestinal Disorders. The largest group of cases, and those 
which from the first have given most support to the theory of the 
cryptogenic origin of the disease, have been referred to disturbance 
of the gastro-intestinal tract. A certain number of these cases have 
shown at autopsy well-marked lesions of stomach or intestines which 
have been deemed a sufficient cause of the anemia, while in others 
the stomach and intestines have been found normal, and the theory 
of intestinal intoxication has been elaborated, principally by Hunter, 
to account for the anemia. Hunter emphasizes the fact that Addi- 
son's anemia, according to its original description, is essentially a 
cryptogenic disease in which the autopsy reveals none of the causes 
assigned by Biermer and others. This group of cases he separates 



PE GBESSIVE PEBNICIO US ANEMIA. 209 

from all others as true Addison's anemia, and for them he finds a 
peculiar etiology in an infectious glossitis and gastro-enteritis. 

1. Lesions of Gasteo-intestinal Tract, Chronic gastritis or 
enteritis with fatty degeneration of the secreting cells of the peptic 
and intestinal glands, followed by atrophy and sclerosis of the mucosa, 
have been demonstrated by Ponfick, J^othnagel, Fenwick, Levy, 
Brabazon, IN^olen, Eisenlohr,^ Osier, Ewald, Martius, Koch, Stengel, 
and Strauss. 

Ewald found this condition of the gastric or intestinal mucosa in 
all his subjects examined at autopsy, and believes that such changes, 
which he calls anadenia, are responsible for all " idiopathic " cases ; 
but Immerman and Quincke had previously shown that anadenia 
is not found in all cases of clearly protopathic origin, and this claim 
has been verified by recent observers. The writer has secured excel- 
lently preserved peptic and intestinal glands and intact lymphoid 
structures from an acute case showing no visceral lesions to which 
the anemia could be referred, and Eisenlohr and Martius have 
reported extensive atrophy of the intestinal mucosa in cases showing 
no gastro-intestinal disturbance and slight anemia. 

Stenosis of the pylorus as a result of annular carcinoma or of chronic 
gastritis, with extreme atrophy and contraction of the stomach, has 
been demonstrated in a considerable number of cases (Israel, Ehrlich, 
Renvers). 

In two of the writer's autopsies the stomach was markedly contracted, the 
pylorus was tightly stenosed, admitting a lead-pencil with difficulty ; the 
mucosa showed the changes of well-marked chronic gastritis, but the constric- 
tion of the pylorus was the result of chronic productive inflammation and not 
of carcinoma. These cases lasted two and four years, with intervals of im- 
provement, but finally died with typical blood changes and without marked 
emaciation. 

Other cases with annular or circumscribed carcinoma of pylorus 
have been reported as showing typical changes in the blood. The 
writer has not yet seen any case of cancer of the stomach in which 
the lesions in the blood were indistinguishable from the classical 
type of progressive pernicious anemia. Lazarus reports genuine cases 
following small pyloric cancers only. 

A " neurotic atrophy " of the intestinal mucosa has been suggested as an etio- 
logical factor by Banti, Jurgens (1882), Blaschko (1883), and Sasaki (1884), 
who found parenchymatous degeneration of ganglion cells in Meissner's and 
Auerbach's plexuses ; but Scheimpflug has shown that no such important 
deductions were warranted from the changes demonstrable at that time in 
sympathetic ganglia, since identical changes occur in many other conditions. 
Peculiar eosinophile globules have been described by Lubarsch, Koch, and 
Sasaki in the atrophic adenoid tissue of chronic gastritis, and these bodies 
have been regarded as pathognomonic of this condition and of significance in 
the anemia ; but Hammarschlag has seen them in gastric cancer and the writer 
in the normal stomach at autopsy one hour after death from ether. 

The mesenteric lymph nodes have been found hyperplastic, in one instance 
caseous, by Eichhorst, Quincke, and others. This condition was present in 
some of the writer's autopsies, but not in all, while in a case of profound sec- 
ondary anemia, probably of syphilitic origin, nearly all the abdominal lymph 
nodes were enlarged and caseous, but there were no megalobhistic changes in 
the blood. 

14 



210 SPECIAL PATHOLOGY OF THE BLOOD. 

It is, therefore, obvious that all the g astro-intestinal lesions thus far 
desoribed in cases of progressive pernicious anemia have been seen in 
other conditions, and that none of them can be regarded as specific 
lesions in the disease. That many of the above lesions, however, 
especially the marked atrophic conditions, may act as occasional 
exciting canses of progressive pernicious anemia, as of secondary 
anemia, seems equally probable; yet not a few observers regard 
them all as secondary to the anemia or as unimportant associated 
lesions, while Faber and Bloch believe that the atrophy of the in- 
testinal mucosa described in many cases is always a cadaveric altera- 
tion. 

2. Functional Distuebances of GxAstro-intestinal Tract. 
The prominence of the gastro-intestinal symptoms of the disease has 
from the first directed special attention to the study of functional 
disturbances in the alimentary tract. 

The reports of Sandoz were apparently the first to seriously 
strengthen the impression that some of the most typical cases of 
pernicious anemia are of intestinal autotoxic origin, this observer 
finding that apparently genuine cases were sometimes cured by 
vigorous gastric lavage, enteroclysis, and the administration of intes- 
tinal antiseptics and laxatives. This observation has since been 
fully verified, and the opinion has steadily grown that the most fre- 
quent, if not the essential, cause of progressive pernicious anemia is 
found in a peculiar toxemia of intestinal origin, with or without 
organic lesions of the mucosa. The evidence supporting this opinion 
has accumulated from many sides. 

The result of intestinal antiseptic treatment has steadily pointed 
in this direction. The observations on bothriocephalus anemia have 
recently given significant evidence to a similar effect (q. v.). Signs 
of increased intestinal putrefaction have been noted in the excessive 
indicanuria of the disease (Senator, Miiller, Brieger, Hennige, 
Grawitz, Schaumann), and in the presence of cadaverin and putrescin 
in the urine of certain cases (Hunter). In a very acute case exam- 
ined at autopsy by the writer the odor of H2S from the intestines 
was very Id tense, but in other cases there was very slight evidence of 
this putrefactive product. Grav/itz* has recently emphasized the 
belief that intestinal toxemia from decomposition of albumins and 
failure of absorption of albumins acting in subjects predisposed to 
anemia are the probable causes in the cryptogenic variety of per- 
nicious anemia. 

3. Specific Infection of the Alimentary Tract. Hunter's 
studies stand practically alone in this field. His conclusions are, 
briefly, that true primary (Addison's) pernicious anemia is a distinct 
pathological condition characterized by excessive hematolysis, occur- 
ring chiefly in the portal system and induced by infection of various 
structures along the alimentary tract with the streptococcus. 

Reviewing the knowledge of the pathological changes in the blood and 
marrow, spleen, and lymph nodes, Hunter concludes that there is no known 
characteristic lesion of the disease, although the high Hb-index of the blood 
he regards as very important and an almost pathognomonic sign. Turning to 



FBOGBESSIVE PERNICIOUS ANEMIA. 211 

the liver he finds in the studies of Peters proof that in the anemia of wasting 
diseases there is no markedly excessive deposit of iron in the liver, and finds 
that in no disease bearing any clinical resemblance to pernicious anemia does 
the deposit of iron in the liver approach in any degree that characteristic of 
pernicious anemia. Moreover, this deposit is largely limited to the outer two- 
thirds of the lobules, a position in which the scanty deposits of other condi- 
tions (extravasation of blood, chronic congestion) are never limited. From 
the comparison of chemical analyses he finds that the liver in pernicious 
anemia contains on the average seven times as much iron as in any other 
diseases attended with anemia, while the iron-content of the spleen is not 
notably increased. He therefore concludes that pernicious anemia consists 
essentially in excessive hematolysis, occurring principally in the liver. Why 
Hunter limits the blood destruction to the portal system is not entirely clear, 
but he reasons as follows: Malaria, paroxysmal hemoglobinemia, and poison- 
ing by pyrogallic acid cause general hemoglobinemia and hemoglobinuria, 
with deposits in the liver unlike those of pernicious anemia, while in this dis- 
ease and in poisoning by toluylendiamin there is never any Hb in the urine, 
but in each case the iron in the liver is found in the same position. Since 
toluylendiamin exerts a specific stimulating action on the liver cells, he 
believes the poison of pernicious anemia must be directed especially against 
the liver, and hence be found principally in the portal system, a source which 
is further indicated by the frequency of gastrointestinal symptoms. 

Hunter's studies are chiefly important in the demonstration of the peculiar 
behavior of the liver in ridding the blood of iron, but the theory of portal 
hematolysis by intestinal intoxication, while doubtless strongly suggested by 
his results, is still far from demonstration. He has recently attributed to bac • 
teria from decaying teeth, streptococci, and to chronic infectious glossitis and 
gastro-enteritis from this source, the essential part in the etiology of the dis- 
ease; but this claim has not been received with much favor on account of 
observations like that of McCrae, who found in forty cases of pernicious 
anemia that oral sepsis was less frequent than in the routine average of hos- 
pital cases. 

Although extensive deposits of iron in the liver and the limitation of the 
pigment to the outer portions of the lobules have since been shown to occur 
in other diseases (Russell, Hindenlang), and cases of pernicious anemia have 
been reported in which no excess of iron was found in the liver (Ransom), 
Hunter has demonstrated characteristic if not pathognomonic features in the 
pathological anatomy of the disease. 

Myelogenous Origin. There are recorded a moderate number of 
observations which suggest that progressive pernicious anemia may 
result directly from lesions affecting the normal physiology of the 
bone-marrow. Fede, Quincke, Krieg, and P. Grawitz have described 
cases of sarcoma of the bone-marrow with the changes of pernicious 
anemia in the blood. Litten (1877) reported a case of pernicious 
anemia followed by leukemia in which there were multiple abscesses 
in the bone-marrow, but the diagnosis of pernicious anemia appears 
doubtful. Waldstein in 1882 saw a similar case in which the marrow 
was the seat of a peculiar change said to have resembled in structural 
details a chloroma found in the mediastinum. 

Grawitz believes that the severe anemia sometimes following infec- 
tious processes is to be referred to changes in the marro^v instituted 
during the course of the infection. The frequent occurrence of per- 
nicious anemia after malaria appears to have similar import. 

Nervous Origin. The prominent participation of the nervous si/stcm 
in the anatomical lesions of the disease has often raised a suspicion 
in many minds that some of these lesions might be primary. Except 
in the case of the abdominal sympathetic, none of the lesions have 



212 SPECIAL PATHOLOGY OF THE BLOOD. 

been long claimed to hold such a position in the pathology of the 
disease, and at present it is generally accepted that the central nervous 
system suffers only secondarily from the anemia or as the result of 
associated conditions. 

Likewise the functional disturbances of the nervous system cannot 
be claimed to act as more than somewhat distant predisposing causes, 
although McKenzie and Curtin have referred to certain cases as 
having originated directly from nervous shock. 

Infectious Origin. Pernicious anemia has not escaped classification 
among infectious diseases : by Klebs, who claimed to have observed 
flagellate bodies in the fresh blood ; by Frankenhauser and Petrone, 
who reported the isolation of leptothrices in several cases ; by Bern- 
heim, who isolated a bacillus from the blood of one case after death ; 
and by Perles, who observed highly refractive, very actively ameboid 
bodies in several cases ; and finally by Hunter. 

Histological Changes in the Marrow. Cohnheim's original 
report on the changes in the marrow of a case of pernicious anemia 
described the presence throughout the shafts of the long bones of 
lymphoid marrow which contained no fat cells, but was composed of a 
small number of colorless myelocytes and of many red cells, most of 
which were nucleated and of unusually large size. This observation 
was verified by many later investigators, especially by Rindfleisch, 
Ehrlich, Muir, Miiller f but its importance was greatly obscured by 
the reports by Neumann, Lit ten, Grohe, and others that chronic 
diseases causing cachexia also lead to a hyperplasia of red marrow 
in the shafts of long bones. Neumann and Litten and Orth claimed 
also to have induced identical changes in the marrow by subjecting 
animals to repeated hemorrhages. In 1886 Geelmuyden claimed that 
the hyperplastic marrow in such chronic diseases does not differ in 
structure from that of normal lymphoid marrow except in regard to 
the Hb-content of the red cells, and that the hyperplasia here repre- 
sents merely a simple physiological increase in functional capacity. 
He showed also that while the hyperplastic marrow in pernicious 
anemia is very extensive, occupying as much as 82 per cent, of the 
cavities of long bones, and is firm and cellular, much of the marrow 
of secondary anemia is apt to be gelatinous, with comparatively few 
cells, while the hyperplasia seldom becomes half as extensive as in 
pernicious anemia. 

The writer, from a study of the marrow in cases of grave secondary 
anemia showing in the blood many megalocytes, observed that the 
limits of the hyperplasia are seldom very extensive ; that the nucleated 
red cells are usually relatively scarce and of smaller size instead of 
being overabundant and of very large size as in pernicious anemia. 
These observations merely corroborate in minor details the original 
claim of Cohnheim and Rindfleisch. 

Yet the essential importance of the changes in the marrow is again 
brought into question by the reports of cases of pernicious anemia in 
which the usual alterations in this tissue are wanting. 

Six such cases, reported by Laache and Quincke, and one by Geelmuyden, 
date from too early a period to figure in the present discussion, but Ehrlich^ 



FSOGBESSIVE PERNICIOUS ANEMIA. 213 

in 1888 reported a case of fatal acute anemia in a "bleeder" who suffered 
principally from metrorrhagia and in whose blood the red cells were reduced 
to 215,000, the majority of them being undersized, while nucleated red cells 
were absent, and there was apparently no hyperplasia of the lymphoid mar- 
row. Engel, Lipowski, and Muir^ have reported similar cases. In 1893 the 
writer^ observed an apparently similar condition in a boy, aged eighteen years, of 
Cuban parentage, who had always appeared pale, and whose sister was ex- 
tremely pale and moderately anemic. The patient suffered from uncontrol- 
lable epistaxis, finally from intestinal hemorrhages, for three weeks before death. 
During the last week the red cells numbered 456,000, the leucocytes were 
reduced in number, there were no megaloblasts and no megalocytes, the 
majority of red cells being oval and undersized. No autopsy was secured, but 
the anemia appeared clearly to be of idiopathic origin. 

Ehrlich, Lazarus, and Engel drew the conclusion from such cases that per- 
nicious anemia is not necessarily associated with hyperplasia of the lymphoid 
marrow. 

The writer has encountered other cases which seem to fall in this class, and 
for which the term " microcytic type of pernicious anemia " has been sug- 
gested, but he has always felt that the grounds for their classification with 
other acute cases showing megaloblasts and megalocytes are at present entirely 
inadequate. The reports of Ehrlich do not offer any evidence to prove the 
relation of these two types of anemia, and it seems entirely premature to draw 
from such cases any conclusions regarding the pathological anatomy and patho- 
genesis of true pernicious anemia. In Muir's case the shafts of the bones were 
thickened, the marrow almost pure fatty tissue, and very few nucleated red 
cells were found in either blood or marrow. 

Tlie extent of the hyperplasia of lymphoid marrow may vary from 
the involvement of the entire shafts of all long bones to the appear- 
ance in smaller foci, only^ of the megaloblastic changes. The latter 
condition is probably seen during the transformation of a grave 
secondary to a pernicious anemia. Hyperplastic lymphoid marrow 
may be found in one long bone, while in others the marrow is normal 
(Lazarus). 

Histologically, the marrow in milder cases shows a considerable 
number of normal red cells, always less than in the circulation, a 
few normoblasts, and a greater number of megaloblasts sometimes 
lying in '^ islands,^^ while in a remarkable case of Rindfleisch's nearly 
all of the cells in the marrow were large megaloblasts. In most of 
the writer's cases the neutrophile myelocytes were distinctly deficient, 
the principal colorless cells being large, hyaline, and mononuclear. 
The eosinophiles are usually deficient. Evidences of active destruction 
of blood cells are seen in the presence of macrophages inclosing many 
red cells, and of many pigmented cells. The megaloblasts may reach 
an extreme size, 50// (Rindfleisch) ; their nuclei are usually eccentric 
and^in various stages of degeneration, while the cell body is polychro- 
matic and very densely staining, or fragmented and pale. 

Not only the grade, but the type of lesion in the marrow appears 
to vary in different cases. The wTiter has encountered three rather 
distinct conditions in the marrow of the ribs, vertebra, and fenuir of 
fatal cases of idiopathic pernicious anemia. 

1. The Cohnheim-Rindfleiscii type (megaloblastic degex- 
eration), in which with wide extension of lymphoid marrow an 
excessive proportion of the cells in the marrow and nearly all the 
nucleated red cells are meoaloblasts or ojo-antoblasts. 



214 SPECIAL PATHOLOGY OF THE BLOOD. 

2. Extreme lymphoid hyperplasia (myeloblastic degen- 
erations^), in which the majority of cells are small, hyaline, and 
mononuclear, while nucleated red cells are scarce, and those remain- 
ing are of large size. This type of lesion is identical with that 
recently described by !N"aegeli under the term " myeloblastic degen- 
eration/' 

According to Naegeli, in pernicious anemia the hyperplastic marrow con- 
tains 95 per cent, of cells, a little larger than lymphocytes, non-granular, 
moderately basophile, with reticulated nuclei. These cells he calls myelo- 
blasts, and claims that they are the ancestral forms of myelocytes. He tinds 
them in small numbers in the blood of pernicious anemia and secondary 
anemia, and very abundantly in leukemia. (Regarding the nature of these 
cells, consult Chapter V.) 

3. Recently the writer encountered a case of fatal pernicious 
anemia of twelve months' duration, without demonstrable origin, in 
which the marrow showed a remarkable excess of nucleated red cells 
of normal size. 

Nature of the Megaloblastic Changes in the Marrow. If Cohnheim's 
belief is accepted that changes in the marrow in pernicious anemia 
constitute a reversion of that tissue to the embryonal type in the 
formation of red cells, pernicious anemia must be regarded as iden- 
tical with or very closely related to a neoplasm involving the red 
cells. This view is accepted by Rindfleisch and Ehrlich, but the 
latter, however, does not apparently press the somewhat strained 
relation to a tumor process. 

The review of our knowledge of the development of the blood, 
contained in Chapter IV., shows that the cellular processes concerned 
in tlie formation of red cells are virtually the same both in adult 
and in fetal life. In both periods the non-nucleated disks are the 
result of mitotic division of several series of erythroblasts, each new 
series containing more and more Hb, until by a process not yet fully 
understood the non-nucleated disk springs from the last series — /. e.y 
the normoblast. In both adult and embryonal lymphoid marrow 
the earlier series of nucleated Hb-holding cells appear to be nearly 
equally represented, while at no period of embryonal life are very 
large mitotic polychromatophilic cells seen such as abound in the 
marrow of acute pernicious anemia, and under no other conditions 
does the marrow contain such an excess of the large megaloblasts as 
in this disease. The essential difference between the normal forma- 
tion of red cells in the adult and their defective development in 
pernicious anemia consists in the failure of the later, more highly 
specialized series of erythroblasts — /. e., the normoblast. This, of 
course, is the fundamental nature of a tumor process, in which the 
highly specialized properly functionating tissues are replaced by 
excessively cellular, poorly differentiated structures, subject to a great 
variety of degenerative changes. 

Although the gigantoblast of pernicious anemia is never seen in 
embryonal blood-forming organs, such aberrant forms seem to result 
from secondary degenerative processes, while it is the absence of 
normoblasts which is the more important anomaly of blood forma- 



PBOGBESSIVE PEBNICIOUS ANEMIA. 215 

tion in the disease. The investigations of the thirty years that have 
intervened since Cohnheim conclnded (1868) that pernicious anemia 
is a reversion to the embryonal type of blood formation seem to have 
in a considerable degree verified his belief. To what extent pernicious 
anemia follows the laws known to govern the occurrence and behavior 
of tumors is an important inquiry which cannot here be further con- 
sidered. 

Pathogenesis of the Disease. Progressive pernicious anemia is believed 
by some to result through defective hematogenesis, and by others primarily 
from excessive hematolysis, to which is added secondarily defective hemato- 
genesis. 

The latter view is based principally upon the abundant evidence of exces- 
sive hematolysis, which is undoubtedly the prominent external feature of the 
disease, upon the reported occurrence of cases of pernicious anemia which 
were rapidly fatal without yielding evidence of defective hematogenesis in 
the megaloblastic changes in the marrow, and upon experimental evidence 
that the prolonged action of certain blood solvents, toluylendiamin, etc., may 
lead to a condition very similar to progressive pernicious anemia. To some 
extent this opinion is favored also by the results of repeated losses of blood, 
which have been shown to lead to a condition closely resembling progressive 
pernicious anemia both in the blood and in the marrow (Neumann). More- 
over, in many cases of grave secondary anemia the blood often approaches in 
character that of the cryptogenic anemia, and this fact has been accepted as 
favoring the hematolytic theory, although in cancer of the stomach, which 
leads to some of the severest grades of secondary anemia, defective blood 
formation seems quite as likely to figure in the anemia as does excessive 
hematolysis. The acceptance of this view involves the admission that the 
changes in the marrow are secondary to the destruction of blood. 

The writer has always felt that the correct conception of the disease accord- 
ing to present knowledge is as a process of defective hematogenesis in which 
megaloblastic degeneration of the marrow is the pathognomonic tissue lesion 
and excessive hematolysis a constant result. 

Hematolysis undoubtedly precedes in many instances defective hemato- 
genesis, but it is a different kind of hematolysis from that which occurs after 
the megaloblastic changes have become established. The peculiar destruction 
of blood cells seen in pernicious anemia, marked by excessive deposits of iron, 
by hemoglobinuria, pathological urobilinuria, by phagocytic englobement of red 
cells in the marrow, and by peculiar clinical symptoms, appears to be possible 
only when red cells are defectively formed. 

Most convincing demonstration of the propriety of this view was encoun- 
tered on comparing a case of profound secondary anemia from chronic ulcer 
of the duodenum with a rapidly fatal case of the cryptogenic disease. In the 
former case, although the Hb registered only 10 per cent, and the red cells 
were below 1,000,000, there were only slight changes in the size of the cells, 
and the patient improved under iron. In the latter case the Hb registered 38 
per cent, on first examination, the red cells 1,780,000; but megalocytes and 
megaloblasts were abundant, and the patient died after an acute illness of four 
weeks. The essential difference between these cases appears clearly to have 
been not in the destruction or loss of blood, but in its formation. 

It has been amply shown that the system can replace enormous losses if 
conditions are favorable for the normal production of blood. Lazarus quotes 
the example of a Russian physician whose health remained little affected by 
the loss of about four times the entire volume of blood by consecutive pul- 
monary hemorrhages in the course of a few months. This author also refers 
to cases of cancer of the stomach in which the anemia remained compara- 
tively harmless until suddenly changing from the secondary type with low 
Hb-index to the primary with'increased Hb-index and appearance of megalo- 
blasts {Die Anaemie, p. 43). 

The attempted experimentar production of pernicious anemia by the use 
of blood solvents, etc., may or may not have been partly successful, as indi- 



216 SPECIAL PATHOLOGY OF THE BLOOD. 

cated by Neumann's studies, but their outcome can hardly alter the fact that 
blood destruction may be continued over long periods without giving the 
typical picture of pernicious anemia which is at once evident in clinical 
observation when defective hematogenesis is added to the long-existent hema- 
tolysis. 

In view of these and many similar considerations it would seem that the 
belief is justified that it is the megaloblastic degeneration of the lymphoid 
marrow which constitutes pernicious anemia a separate clinical and patho- 
logical entity. Hematolysis may and in some instances does precede, in point 
of time, the changes in the marrow, as in the pernicious anemia following 
malarial cachexia ; but this destructive influence at once takes on a new char- 
acter and produces specific results when acting on defectively formed cells, as 
is shown by the comparison of the iron-content of the liver in secondary and 
in progressive pernicious anemia. 

The occurrence of rapidly fatal cases of the disease and the transformation 
of a grave secondary anemia (cancer of pylorus) into true pernicious anemia 
may be explained by a rapid and general or slow and partial establishment 
of the marrow changes. In the former case the changes in the blood will be 
pronounced from the first ; in the latter it m ay be difiicult to determine the 
exact point when a grave secondary becomes a true pernicious anemia. 

Changes in the Blood. 

Chemistry. The specific gravity of the blood is constantly 
reduced, owing to the loss of both the albumins of the plasma and 
the Hb of the red cells. The gravity is here a much less reliable 
indication of the Hb-content than in chlorosis, in which the Hb alone 
is markedly affected (Hammarschlag, Dieballa). ]N"evertheless, it is 
just in this disease that the information furnished by the specific 
gravity is of peculiar interest, as it concerns those principles in the 
plasma of which little can be learned by other, simple clinical tests. 

Grawitz finds that the specific gravity of the blood may fall below 
1.030, or below that of normal serum. Dieballa had two cases 
showing a gravity of 1.028, with red cells 404,000 and 500,000; 
while Copeman, using Roy's method, reported a case with a gravity 
of 1.027. That there is no close relationship between the numbers 
of red cells and the specific gravity appears in Dieballa's tables, in 
which a gravity of 1.038 was obtained in one case showing 784,000 
cells and in another with 1,400,000 cells. The total albumins of 
the blood are much reduced, but the loss affects principally the red 
cells. Grawitz finds the loss of albumins of the serum to be dis- 
tinctly greater m secondary anemia than in progressive pernicious 
anemia. 

The great reduction In total albumin of the blood is indicated by 
the low percentage of dry residue found by v. Jaksch, Grawitz, and 
Stintzing and Gumprecht, who in very severe cases obtained between 
9 and 12 per cent, (normal 20 to 24 per cent.), while the red cells 
numbered between 534,000 and 1,700,000. That the loss of albumin 
is due principally to the changes in the red cells appears from the 
fact that the specific gravity and dry residue of the serum are but 
slightly altered even in severe cases 

Thus Grawitz found a gravity of the serum of 1.024 (normal, 
1.027 to 1.029), dry residue 7.08 per cent, (normal, 10 to 10.5 per 
cent.), while the gravity of the blood fell to 1.036, and its dry resi- 



PBOGBESSIVE PERNICIOUS ANEMIA. 217 

due to 11.45 per cent, (normal, 21 to 24 per cent.). While the 
albumins of the blood were reduced, therefore, one-half, those of tlie 
serum fell only one-fifth. Similar results were obtained by Dieballa. 
This loss of albumins of the whole blood must be referred to the 
loss of fibrinogen and to the diminution of red cells, v. Jaksch's 
analyses^ of red cells in pernicious anemia led him to conclude that 
those remaining are abnormally rich in albumins — a view which 
may seem to accord with the large size of these cells. By estimating 
the N of 100 grs. of centrifuged red cells he obtained 6.48 grms. 
N, 40.5 grms. albumin (normal 34.5). Grawitz's analyses, however, 
do not support this conclusion. 

The relatively high proportion of albumin in the serum in perni- 
cious anemia distinguishes this disease, as Grawitz has shown, from 
many forms of secondary anemia arising from hemorrhage, malignant 
tumors, etc., with which the albumins of the serum are much 
reduced. 

The resistance of the red cells has not apparently been tested, 
although Limbeck (p. 163) found their isotonc tension somewhat 
increased (resistance diminished) in two cases of grave anemia. 

Copeman noted that the hemoglobin crystallized readily from the 
blood of a case of pernicious anemia, while it is very difficult to 
obtain such crystals from normal human blood. 

Morphological Changes. The whole blood is much reduced 
in quantity, as is shown by the scanty content of vessels and viscera 
at autopsy and by the imperfect filling of the superficial vessels during 
life. This reduction in bulk is often so marked as not to require for 
its demonstration any attempts at accurate measurement. 

Smith's conclusion that the volume of blood in pernicious anemia is increased 
strongly suggests that in this disease his method of determination by the oxygen 
capacity is unreliable. 

Coagulation is very feeble, so that on standing it was early 
noted (Ponfick) that the red cells settle to the bottom, the leucocytes 
form a middle layer of variable depth, while the plasma deposits 
nearly all its cells without interference from clotting. To the feeble 
clotting is probably referable the very slow separation of serum from 
the clot, as observed by Lenoble. 

The COLOR of the blood may in mild cases be almost normal ; it 
is usually very pale ; while in extreme cases visible currents of color- 
less serum mingle with the drop on very slight pressure. On this 
account a liberal puncture may be required to obtain a drop suitable 
for examination. A very dark color has been observed by Furbrin- 
ger and, after transfusion, by Gusserow. 

Hemoglobin. The percentage of Hb varies from a moderate reduc- 
tion (70 per cent.) to such a low point that accurate estimates are 
impossible, while the Fleischl instrument indicates less than 10 per 
cent. In the average cttse the Hb registers between 20 and 40 
per cent. A rather high percentage of Hb with severe clinical symp- 
toms and pronounced morphological changes in the red cells is not 
infrequently seen. Lazarus refers to a case showing 65 to 70 per 



218 SPECIAL PATHOLOGY OF THE BLOOD. 

cent., but otherwise with pronoanced symptoms. The Hb is usually 
not so low as in secondary anemias of equal severity. 

A KELATIVELY HIGH Hb-index is One of the characteristic 
features of the blood. In many cases, especially when the megalocytes 
are very abundant, the Hb-index is above normal (1 to 1.75), and in 
such cases the index is apt to rise as the anemia increases, and to fall 
during intervals of improvement. In a larger group of cases the 
index does not vary greatly from the normal, when the excess of 
Hb in megalocytes balances the loss in other cells. In other cases 
the index is for long periods below normal, but still relatively high 
as compared with secondary anemia and chlorosis. Thus the Hb- 
index in chlorosis averages about 0.50 (Cabot, Bramwell), but in 
pernicious anemia the index seldom appi^oaches that figure. The low 
Hb-index is usually seen in chronic cases, while the highest indices 
obtained by the writer were in more rapid cases especially just before 
death. 

In some cases of secondary anemia the Hb-index may approach 
the normal, so that comparatively little diagnostic importance can 
attach to the lesser grades of increase in Hb. 

Red Cells. In the average case of established pernicious anemia 
the red cells vary slightly above or below 1,000,000. Well-marked 
morphological changes may exist, however, when the red cells 
number over 2,000,000 ; but earlier stages of the disease have so far 
escaped notice, indicating that pre-existing anemia is an essential 
predisposing condition. 

Although Quincke reported 143,000 red cells in a case which 
recovered and Hayem 292,500 in a fatal case, more recent reliable 
statistics show that life is seldom prolonged when the cells fall below 
400,000. Even this extremely low proportion is below the count in 
many fatal cases, as many patients succumb when the red cells are 
about 1,000,000. Most fatal cases show at death between 300,000 
and 600,000 red cells. The reduction in cells, in cases under treat- 
ment, seldom progresses uniformly, intervals of improvement, fol- 
lowed by rapid relapses, continuing until the end. 

Changes in the form, size, and stain'mg reaction of the cells are 
even more important than their reduction in number. 

While the largest cells of normal blood measure about 9/^ across, 
in pernicious anemia the increased size of the cells is characteristic 
of the disease, the average diameter being estimated by Lazarus at 
11 pi to 13//, w^hile some may reach a diameter of 16^m to 18^« (Aska- 
nazy). Cases vary greatly in regard to the extent and uniformity 
of this lesion. In one of the Avriter's cases, not of unusual gravity, 
at least 90 per cent, of the cells measured from 11 fj. to IQfj.. Mega- 
loblasts were very numerous, and microcytes extremely rare. It 
may he said that unless 33 per cent, of the cells are distinctly oversized 
the diagnosis of pernicious anemia should he made ivith reserve. Usually, 
but not always, the proportion of megalocytes accords with the 
severity of the condition. Lazarus found in eight severe cases 56 
to 71 per cent, of megalocytes, in five cases during periods of improve- 
ment 33 to 50 per cent., or during complete remissions to 14 per cent. 



PLATE VI 





w^ 4 




Progressive Pernicious Anemia. (Eosin and Methylene Blue.) 



Fig. 1. Megalocyte with excess of Hb. 

Figs. 2. Microcyte with excess of Hb. 

Fig. 3. Microcyte deficient in Hb. 

Fig. 4. Poikilocyte deficient in Hb. 

Figs. 5. Poikilocyte with excess of Hb. 

Fig. 6. Polychromasia of Maraghano. 

Fig. 7. Megaloblast, resting vesicular nucleus, baso])hiUc granules in cytoplasm. 

Fig. 8. Microblast. , 

Fig. 9. Megaloblast in mitosis. Thread stage. 

Fig. 10. Megaloblast. Pathological mitosis. 



PBOGBESSIVE PEBXICIOUS ANEMIA. 219 

The Hb-content of these megalocytes is in typical cases distinctly 
increased and the cell is flat and uniformly opaque instead of show- 
ing the biconcave discoid shape. The writer has found this character 
of the megalocytes a very reliable differential sign between true 
pernicious anemia and the grave secondary anemia of cancer, etc. 
In the latter conditions the great majority of megalocytes are usually 
deficient in Hb. (Cf. Plates YI. and YII.) ^ 

MiCROCYTES are a somewhat less characteristic cell -form in perni- 
cious anemia. They may be only slightly under normal size or be 
found in severe cases as mere points of reddish staining protoplasm 
not over 1(2 in diameter. They may contain an excess or deficiency 
of Hb. In the early stages of the disease the writer has found them 
less frequent, but in moribund cases they rarely fail to appear in 
considerable numbers. The division of forms between megalocytes 
and microcytes is then often complete, no normal cells remaining. 

Deformed red cells (poikilocytes) of all sizes are commonly 
present in considerable numbers, probably resulting from the ameboid 
properties of the cells and frequently from traumatism. The oval 
shape of many cells both large and small was early noted by Osier 
and Gardner, but this type of cell is much more characteristic of 
purjDura hcemorrhagica. Pear-shaped cells are perhaps the most 
common form, the narrow point representing a pseudopodium. 
Cells very deficient in Hb are apt to bend into horseshoe or pessary 
shapes. Cells rich in Hb less often become deformed. 

Ameboid motion of red cells in pernicious anemia may be observed 
in fresh preparations. The moving cells usually content themselves 
with the extrusion of pseudopodia, and with changes in shape Avhich 
Muir and Gulland believe are not true ameboid phenomena, but the 
writer has seen active locomotion of lenticular microcytes. 

Nucleated red cells may be said to occur in all cases of per- 
nicious anemia, but their demonstration sometimes requires prolonged 
search. It has been shown by Ehrlich and verified by nearly all 
later observers that megaloblasts constitute the majority of such cells 
in pernicious anemia, and there is at present no ground on which to 
deny their pathognomonic significance, when present in large num- 
bers. In typical cases of the disease they are almost or quite 
exclusively present, while normoblasts are scarce. Their numbers 
seem to depend largely on disturbances of the circulation and other 
accidents ; but Ehrlich claims that the extent of the megaloblastic 
degeneration of the marrow may be determined by the numbers of 
these cells in the blood. This rule probably holds in general, but 
in the writer's experience there have been exceptions. In other 
cases both normoblasts and megaloblasts appear in the blood, in 
which case it is found that the megaloblasts outnumber the normo- 
blasts, indicating that the defective formation of cells has become 
uppermost. 

From the considerations mentioned under the etiology and patho- 
genesis of the disease, it will be seen that the crucial point in the 
diagnosis between secondary and pernicious anemia is encountered in 
practice, in the proportions of normoblasts and megaloblasts to be 



220 SPECIAL PATHOLOGY OF THE BLOOD. 

found in the blood. If, as appears to be fally attested, a grave 
secondary may be transformed into pernicious anemia, the change 
must consist primarily in a megaloblastic degeneration in some por- 
tion of the marrow. The normoblasts of the circulation must then 
be gradually replaced by megaloblasts. 

These theoretical deductions appear to be borne out in clinical experience 
since the appearance of megaloblasts accompanies a more severe type of 
anemia. Lazarus finds normoblasts rarely associated with megaloblasts, and 
this has been the writer's experience, except in children, in whom both are 
frequently found together. Schaumann saw both forms in all his cases of 
bothriocephalus. Cabot noted that megaloblasts and normoblasts are frequently 
associated in pernicious anemia and that the former increase when the disease 
grows worse. Askanazy found many megaloblasts in a case of bothriocephalus, 
while after expulsion of the worms they were steadily replaced by normoblasts. 
Dorn observed an idiopathic case promptly improve after the sudden appear- 
ance of many normoblasts. From Ooles' and Solley's observations it is seen 
that there may be very marked variations in the numbers and to a less extent 
in the proportions of normoblasts and megaloblasts in the blood, and that in 
the early stages of the disease normoblasts may predominate. On both clinical 
and pathological grounds, therefore, it is justified to class an anemia as per- 
nicious when the megaloblasts outnumber the normoblasts, or when any con- 
siderable proportion (33 per cent.) of the red cells are megalocytes with 
increased Hb. The writer has encountered clinically and at autopsy cases of 
cryptogenic pernicious anemia in which very large numbers of erythroblasts, 
of normoblastic or slightly larger size, were present in the blood and the 
marrow. 

A question frequently arises regarding the value of a prolonged 
search for megaloblasts in order to establisli the diagnosis of pernicious 
anemia, since if only one nucleated cell be found and that a megalo- 
blast, the chances favor the presence of an excess of such cells over 
normoblasts. It is quite possible, however, that the first few nucleated 
cells should be of large size, while the next three or four prove to be 
normoblasts, and it appears much more rational to base the diagnosis 
upon the general morphology of the blood and on all clinical data, than 
to rely upon any single isolated sign. JSTevertheless, the discovery of 
a single very large megaloblast with abnormal nucleus is virtually a 
pathognomonic sign of pernicious anemia. Especially significant is 
the discovery of megaloblasts in which the nucleus constitutes four- 
fifths of the cell, and is reticular in structure instead of compact, 
and in which the cytoplasm is strongly polychromatic (EngeFs 
metrocyte). 

The numbers of nudeaied red cells in pernicious anemia vary greatly. 
Frequently they are scarce and their demonstration requires patient 
searching. Or, of two slides taken at the same time one may con- 
tain several and the other apparently none. Usually they increase 
with the severity of the blood changes. The occurrence of normo- 
blastic blood crises has been referred to as a favorable sign (Dorn). 
Coles found over 6000 nucleated red cells per c.mm., the majority of 
large size, in a fatal case, and Solley found 35,000, mostly normo- 
blasts, shortly before marked improvement in the blood of a case of 
ascariasis with pernicious anemia. Straus and Rohnstein followed a 
case in which only normoblasts were present until shortly before 
death, when very large numbers of megaloblasts suddenly appeared 



PLATE Vll. 




Secondary Pernicious Anemia. (Eosin and Methylene Blue.) 



Figs. 1. Megalocyte. 

Fig. 2. Red cells of normal size deficient in Hb. 

Fig. 3. Microcyte deficient in Hb. 

Fig. 4. Red cell showing granular degeneration. (Punctate basopliilia.) 

Fig. 5. Megalocyte with excess of Hb. (Polychromasia of Gabritschewsky.) 

Fig. 6. Polynuclear leucocyte. Nodal points of cytoretioulum. 



PROGRESSIVE PERNICIOUS ANEMIA, 221 

in the blood. The writer has found them unusually abundant in a 
case in which nearly all the red cells were very large^ and has seen 
them nearly as numerous as the leucocytes during antemortem leuco- 
cytosis. Distinct microblasts are comparatively rare. 

The occurrence of mitotic nuclei in megaloblasts, first described by 
Luzet, is usually limited to the severer stages of the disease, in which 
their presence is pathognomonic of the condition. Schaumann, how- 
ever, found them in a case that recovered. The presence of three or 
more unequal asters in one gigantoblast, as occasionally found in 
severe cases, is one of the most significant pathological signs within 
the range of blood analysis. (Plate YL, Fig. 10.) 

Degenerative changes in the red cells not only cause the 
appearance of abnormal cell forms, but lead to a series of chemical 
and morphological alterations plainly demonstrable in stained speci- 
mens. Polychromatophilia, referring to the development of a brownish 
staining quality of the Hb, is constantly present, usually more marked 
in the severer cases It appears probable that the change is in some 
cells preliminary to the solution of Hb in the plasma, but, according 
to Engel, it indicates very rapid formation of cells and incomplete 
metamorphosis of nucleus. It is most marked and nearly constantly 
present in megaloblasts, some of which stain diffusely brownish blue. 

Hemoglohinemia is constantly present in the severer cases and is 
indicated by a distinct brownish red staining quality of the dried 
plasma. 

Punctate basophilia (granular degeneration, Grawitz^) of red 
cells is of moderately frequent occurrence, both in megalocytes and 
especially in megaloblasts. As previously shown, this abnormality is 
sometimes referable in the megaloblasts of pernicious anemia to kary- 
orrhexis of degenerating nuclei. In other cells the blue granules are 
probably reappearing particles of the nuclear remnant of ordinary 
red cells (Maximow). 

ScHiSTOCYTOSis, or the separation of fragments of red cells, is, 
according to Ehrlich, the mode of origin of many microcytes in per- 
- nicious anemia. 

Hydremia of red cells probably causes many smaller cells to appear 
much larger than normal It has already been shown that hydremia 
of the plasma is probably responsible for the increased diameter of 
many red cells, but in pernicious anemia the majority of megalocytes, 
especially those with increased Hb, are undoubtedly derived from 
megaloblasts. 

Absence of rouleaux is a constant and very characteristic 
feature of the disease, and results not only from the reduction in the 
number of cells, but principally from chemical changes in their mem- 
branes and protoplasm. 

The Leucocytes. In well-established cases the leucocytes are 
markedly reduced in number. This condition is clearly referable to 
the megaloblastic lesion in the marrow, which leads to an excessive 
proliferation of megaloblasts at the expense of other marrow cells 
(Rindfleisch). Progressive hypoleucocytosis is the rule, the white 
cells falling very low in extreme cases (1500 to 2000, Hay em). Of 



222 SPECIAL PATHOLOGY OF THE BLOOD. 

the colorless cells which remain, a diminished proportion are neutro- 
phile, the majority being large and small basophilic cells. With the 
reduction in total numbers there is a relative lymphocytosis, very 
slight in the mild cases and very marked (85 per cent., Da Costa; 
90 per cent., Geissler) in severe stages. The eosinophile cells usually 
vary within low normal limits. In the severer cases they are apt 
to be reduced (Grawitz), and rarely may be absent (Cabot) ; but, con- 
trary to Neusser's belief, they are very scarce in mild and present 
in some fatal cases. In the marrow, the writer has found them 
usually much reduced in number. Ilyelocytes are usually present in 
small numbers, Cabot finding them in forty-two of fifty-two cases, 
and Da Costa in twenty-nine of thirty-one cases. The writer finds 
these cells in pernicious anemia almost invariably of the smaller type, 
but has seen isolated specimens of the larger (CorniPs) neutrophile 
cell, which is abundant in leukemia. 

Mast-cells were increased in some of the writer's marrow smears, but 
he has never seen more than single examples in the blood smear. 

Hyperleucocytosis in pernicious anemia occurs as the result of com- 
plications, as an antemortem phenomenon, rarely without discoverable 
cause in course of the disease, and in one case (Dorn) it appeared to 
be associated with a normoblastic blood crisis, and heralded a favor- 
able turn in the disease. In many of these cases the leucocytosis is 
very marked and so many myelocytes or lymphocytes are present as 
to lead to the diagnosis of acute leukemia. Thus Geissler found 90 
per cent, of lymphocytes among 34,000 cells in one such case, and 
Grawitz* reports 20 per cent, of myelocytes among 55,000 white cells 
in another, while Freund counted 25 per cent, of these cells in a 
chronic case and Arneth 14 per cent, in an acute case. The occur- 
rence of such changes in the blood of pernicious anemia should be 
carefully considered when a diagnosis of acute leukemia is suggested. 

There have recently appeared rather numerous reports of acute lymphatic 
or myelogenous leukemia without leukemic lesions in the viscera. An exami- 
nation of several of these reports shows that the writers have been dealing 
with cases similar to those which Grawitz and others described as pernicious 
anemia with leucocytosis and high proportions of myelocytes or lympho- 
cytes. There can be little doubt that Grawitz's interpretation of these cases 
is the correct one, and that without specific lesions in the viscera leukemia 
cannot exist. 



RESUME OF THE CHIEF FACTS CONCERNING PROGRESSIVE 
PERNICIOUS ANEMIA. 

Definition. The term should be applied to all forms of grave 
anemia showing megaloblastic or myeloblastic degeneration of the 
bone-marrow, a lesion which is usually accompanied by an excess of 
megaloblasts over normoblasts in the blood, or at least 33 per cent, 
of megalocytes (or less during remissions). 

Etiology. The largest group of cases remains of cryptogenic 
origin, but is possibly to be referred to intestinal intoxication. 
A^arious lesions of the gastro-intestinal tract are underlying causes. 



PEOGBESSIVi: PERNICIOUS ANEMIA. 223 

including chronic gastritis with or without stenosis of pylorus, and 
small carcinomata of pylorus. 

Of intestinal parasites, Bothriocephalus latus frequently, and other 
parasites occasionally, lead to the disease. 

JRepeated hemorrhages in rare instances cause typical pernicious 
anemia. Pregnancy has no specific influence, but the cases which 
follow parturition are probably referable to hemorrhage and various 
unhygienic conditions. 

The disease is referable to pernicious malaria often ; to syphilis, 
jorolonged diarrhea, had hygienic conditions, probably ; to typhoid 
fever, yellow fever, and other infectious diseases, doubtfully ; but 
not to functional or organic disturbances of the nervous system. 

Lymphosarcoma of the marrow was present in one reported case. 

Pathological Anatomy. The essential lesion of the disease is a 
megaloblastic metaplasia of the lymphoid marrow which is invariably 
present, is pathognomonic of the disease, and in many respects resem- 
bles a tumor formation affecting the progenitors of the red cells. 

Pathogenesis. The disease does not exist until defectively formed 
red cells are being destroyed in large numbers by some hemolytic 
agent. 

Changes in the Blood. The red cells may be reduced to about 
200,000, but usually number about 1,000,000. Megalocytes with 
increased Hb constitute from 33 per cent, to 90 per cent, of the cells, 
but during remissions they may. be very scanty. 

Megaloblasts are very scarce, or very numerous, and are either 
exclusively present or outnumber the normoblasts. During remis- 
sions normoblasts maybe the more numerous. Microblasts are rare. 

The Hb-index varies, but in the advancing stages it is usually 
above normal, or during periods of improvement or remission may 
be below normal. If below normal, it is usually higher than in any 
other form of anemia. 

In the fresh blood coagulation is very feeble, rouleaux do not form, 
there are doubtful evidences of ameboid motion of poikilocytes, but 
occasionally active locomotion of microcytes. Hemoglobinemia often 
exists, but is sometimes, possibly, an artifact. 

Degenerative changes in red cells are extensive, including poikilo- 
cytdsis, schistocytosis, diminished resistance and solution of red cells, 
polychromasia(Grabritschewsky), punctate basophilia, and karyorrhexis 
in megalocytes and megaloblasts 

Leucocytes are usually reduced in proportion to the severity of the 
lesion in the marrow and the progress of the disease, and relative 
lymphocytosis is the rule. Leucocytosis arises usually from compli- 
cations, rarely with ^^ blood crises/' and often just before death. 
Eosinophiles are commonly deficient and a few medium-sized myelo- 
cytes can usually be found. Either lymphocytes or myelocytes may 
be found in such proportions as to suggest leukemia. 

Chemistry. The blood is much reduced in bulk. The specific 
gravity has no constant relation to the number of red cells or propor- 
tion of Hb, but follows the loss of albumins, of cells, and of plasma. 
It may fall as low as 1.027. The albumins and specific gravity of 



224 SPECIAL PATHOLOGY OF THE BLOOD. 

the serum are much less reduced than in grave secondary anemias. 
The resistance of the red cells is reduced and Hb may crystallize 
readily. The hydremia of the plasma affects the red cells and is 
probably responsible for some of their increase in size. 

The diagnosis 7nay rest upon the presence of numerous megalo- 
blasts and megalocytes with increased Hb ; 33 per cent, of megalo- 
cytes with increased Hb ; an excess of megaloblasts over normoblasts ; 
a single gigantoblast or megaloblast in pathological mitosis. 

The diagnosis canniiot rest on an extreme reduction of red cells. 

The diagnosis may require the complete summation of all clinical 
and morphological data, as well as observation on the course of the 
disease, or even the microscopic examination of the marrow. 

The cases of fatal idiopathic anemia of microcytic type (Ehrlich, 
Engel, and others) cannot at present be classed with the Addison- 
Biermer progressive pernicious anemia. 

The prognosis is very difficult to determine. 

The most severe case on record recovered (Quincke's with 
143,000 (?) red cells). Severe cases of cryptogenic origin may 
recover. The most unfavorable are the very acute idiopathic cases, 
and those of slower development from gastro-intestinal lesions. 

The sudden development of well-marked changes in the blood 
commonly indicates a severe course, but such cases have recovered. 
The slow relapsing cases, with gradual changes in the blood and 
absence of megaloblasts usually die from their anemia. 

A high Hb-index goes with well-marked changes in the blood 
and marrow and is of unfavorable import. Lower Hb-indices 
are seen in chronic cases and in remissions of more acute cases. 

A reduction to 600,000 to 700,000 red cells in this disease is 
seldom survived. Marked degenerative changes in megalocytes and 
megaloblasts and marked hemoglobinemia go with the severe cases. 

Extreme reduction of neutrophile and eosinophile leucocytes is an 
unfavorable sign ; while leucocytosis commonly precedes death by a 
few days. 

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15 



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Sasaki. Virchow's Archiv, 1884, p. 96. 

Schehy-Buch. Deut. Archiv klin. Med., 1876, Bd. 17. 

Scheimpflug. Zeit. f. klin. Med., 1885, Bd 9, p. 58. 

Scheperlen. Schmidt's Jahrb., 1880, Bd. 186, p. 22. 

Senator, Muller. Virchow's Archiv, Bd. 131, Suppl. 

.Solley. Presby. Hosp. Reports, vol. v. p. 189. 

Sorensen. Virchow's Jahresbericht., 1874, II., p 314. 

Stengel. Therapeutic Gaz., 1894, p. 378. 

Stintzing, Gumprecht. Deut. Archiv klin. Med., Bd. 53, p. 265. 

Stockman. Brit. Med. Jour., 1895, I., pp. 965, 1025, 1083. 

Strauss. Berl. klin. Woch., 1902, p. 798. 

Strieker. Charite-Annalen, 1875 Bd. 2, p. 277; 1877, p. 287. 

Wagner. Archiv f. phys. Heilk., 1859, p. 415. 

Waldstein. Virchow's Archiv, Bd. 91. 

Wilks. Guy's Hosp. Rep., 1857, p 203. 

Zappert. Wien. klin. Woch., 1892, p. 347. 

Zenker. Deut. Archiv klin. Med., 1874, Bd. 13, p. 348. 



CHAPTEE VIII. 

LEUKEMIA. 

Historical. Probable cases of leukemia were observed and com- 
mented upon from the beginning of the nineteenth century by Bichat 
(1801), Andral (1823), Hodgkin (1832), Donne (1830), and many 
others, and the disease was imperfectly recognized in current text- 
books (Piorry, Velpeau, Pokitansky), m which it was regarded as an 
obscure suppurative ^' hematitis ^' (Piorry). Donne, however, in 
1839, found in his case at autopsy that the blood cells were more 
than one-half " white or mucous globules," and attributed the dis- 
ease to a failure of transformation of the leucocytes into red cells. 

The first step in the elucidation of the disease was made when 
Craigie, in 1841, demonstrated an entire absence of suppurative foci 
in the body and concluded that the purulent material was absorbed 
from the enlarged spleen, of which the histologial structure " does not 
favor the gathering of pus in abscesses." 

In the same issue of the Edinburgh Ifedical Journal Bennett 
described a second case, demonstrating an entire absence of suppura- 
tive foci, describing accurately the gross appearance of the blood in 
bulk, and under the microscope recognizing the leucocytes as iden- 
tical in appearance with pus cells, and adding to the lesion in the 
spleen a uniform enlargement of lymph nodes. Regarding the nature 
of the disease he concluded that the excess of leucocytes in the blood 
must be classed as pus ; that in this case the pus was formed, entirely 
from the action of a zymotic principle in the blood, quite apart from 
inflammatory processes ; and that the enlargement of the liver and 
spleen and the pyoid condition of the blood " lead us to conjecture 
that in some way they stand in the relation of cause and effect." 

Yirchow, a few weeks later, described a case complicated by 
superficial abscesses, and termed the condition " tveisses blut^' or 
leukemia. In a series of later articles he distinguished more clearly 
than Bennett had done between pyemia and leukemia, and empha- 
sized the relation between the changes in the blood and the lesions 
in the blood-forming organs, holding the disease to be a primary 
affection of these organs. 

In 1851 Bennett contributed the first monograph on the disease, 
collecting thirty-seven cases, describing and depicting the micro- 
scopic appearance of the blood, reporting the first chemical analyses, 
giving very reliable descriptions of the symptomatology and patholog- 
ical anatomy, reporting cases of idiopathic splenic tumor without leu- 
kemia, and employing the term leucocythemia as preferable to leukemia. 

In 1847 Virchow observed a case in which the spleen was very 
slightly and the lymph nodes greatly enlarged, and in his review of 



228 SPECIAL PATHOLOGY OF THE BLOOD. 

the subject in 1853 he pointed out the grounds for division of the 
disease into splenic and lymphatic varieties. The chief of these 
grounds was the presence in the blood of the above case of cells 
which resembled those of the lymph nodes. 

The leucocytosis was first demonstrated during life by Fuller 
(1 846), who also believed that the alterations in the blood were not 
of inflammatory origin. In 1851 Yogel also demonstrated the 
leucocytosis during life and attempted to count the cells. 

In 1869 IN'eumann^ described the lesions of the marrow, demon- 
strating the origin of the myelocytic variety of the disease, and his 
observations were verified and extended by AValdeyer (1871). Pon- 
fick noted that in some cases the marrow is light yellow and puriform, 
while in others it retains more or less fleshy color, a variation which 
he referred to the extent of the cellular hyperplasia. The hyperplasia 
of the gastro-intestinal lymphatic structures and metastatic tumors of 
the pleura were described by Friedrich in 1857, while the enlarge- 
ment of the liver was referred to collections of cells probably derived 
from the blood, by Bottger, in 1858. 

In the morphology of the blood it was shown by Bennett and 
Yirchow that the leucocytes of the blood were identical in appear- 
ance with those of pus, although Yirchow was careful to point out 
that they were not therefore of similar significance These early 
observers both described the cells as mononuclear or poly nuclear, or 
devoid of nucleus (Yirchow) and granular or hyaline. Yirchow 
and most others mistook the eosinophile granules for fat particles. 
In his case of lymphatic leukemia Yirchow describes the cells of the 
blood as resembling those of the lymph nodes. 

No important advance in the knowledge of the minute structure of 
leukemic blood cells was made until Schultz and Erb, in 1865, clas- 
sified leucocytes according to the character of their protoplasm. 
Neumann's discovery of the myelocytic type of the disease also 
directed more careful attention to the characters of the new leuco- 
cytes and strengthened the suspicion that the new cells of leukemic 
blood were not all of the same varieties as seen in normal blood. 
The question was finally settled by Mosler,- who punctured the 
sternum during life and secured from the marrow large numbers of 
the identical cells seen in the peripheral circulation. It was at once 
concluded that these cells must be characteristic of the myelogenous 
type of the disease. 

In 1878 Neumann contributed an important study claiming that 
some cases are of purely myelogenous origin, that in no case is the 
marrow uninvolved, and that a lesion of the spleen or lymph nodes 
alone is incapable of producing the disease. The most recent studies 
of the disease have tended to support this belief, that leukemia of 
both types is always of myelogenous origin (AYalz, Pappenheim, 
Hirschlaff, and Kormoczi). 

In 1879 and 1880 Ehrlich's studies added greatly to the knowledge 
of leukemic changes in the blood, and were especially important in 
permitting greater accuracy in diagnosis. It, then, for the first time, 
became possible to distinguish all cases of lymphatic from myelocytic 



LEUKEMIA. 229 

leukemia and to recognize early stages and other obscure phases of 
the latter type of the disease. The first pure case of myelocytic 
leukemia was described by Litten/ 

In the diagnosis of myelocytic leukemia Ehrlich was able to find 
in the blood three chief signs : (1) mononuclear cells with neutro- 
phile granules, (2) an increased number of eosinophile cells, and (3) 
normoblasts or, later, megaloblasts. 

His conclusion that an increase of eosinophile cells, first noted by 
Jaderholm and Schwarze, is pathognomonic of the disease was soon 
relinquished. As shown by Miiller and Rieder, it is not so much the 
increased numbers, but the peculiar forms of eosinophile cells which 
are characteristic of leukemia, although their numerical excess is 
often of itself pathognomonic. The neutrophile myelocytes, as long 
before claimed by Mosler, were therefore again accepted as the most 
important cell form. Through the contributions of Mosler,^ Ehrlich, 
Oornil, Miiller/ Limbeck, Rieder, Troje, and many others, it was 
shown that these cells are derivatives of the marrow and probably 
peculiar to the blood of leukemia. The diagnostic importance of 
Cornil's large myelocytes with pale eccentric nucleus was established 
through the observations of Eberth, Eisenlohr, Mosler, Litten, 
Hay em, and especially of H. F. Miiller. 

Later it came to be recognized that neutrophile myelocytes are 
occasionally seen in small numbers in many other conditions. Con- 
sequently there remained, as a diagnostic feature of the blood, only 
the presence of a large proportion of myelocytes, and it was seen that 
the genuineness of some previously reported cases was open to doubt 
(e. g., Litten's). 

Diminution or absence of ameboid motion in the myelocytes of 
leukemia was described by Biesiadecki, Lowit,^ Hayem, Miiller, 
Gilbert, Rieder, and others. That this loss of ameboid motion is 
associated with a loss of reproductive capacity was stated by Mayet.^ 
A partial loss of ameboid activity of other leucocytes was observed 
by Neumann and Cavafy, while J. Weiss does not admit any differ- 
ence in ameboid properties of the white cells of leukemia and of 
other leucocytes. Jolly depicts slow ameboid movements of both 
neutrophile and eosinophile myelocytes in leukemic blood at 38^ C. 

The discovery of nucleated red cells was followed by their demon- 
stration in the blood of leukemic cadavers by Erb, Bottger,^ and 
Klebs,^ and in the circulating blood by Neumann.^ The comparative 
absence of these cells in lymphemia was first noted by Hayem and 
verified by Wertheim, Rieder, and Dock. Megaloblasts were first 
distinguished in leukemia by Ehrlich's pupil, Utheman, and bv 
Troje. 

Likewise the discovery of mitotic division of leucocytes by Flem- 
ming and Arnold led, after a time, to the demonstration of mitotic 
figures in the white cells of both the viscera and the blood of leu- 
kemia (Arnold, 1884; Hayem, 1889 ; H. F. Miiller, 1889). 

Acute leukemia was first described by Friedrich in 1857 in a case 
lasting six weeks. Other reports of similar cases were added slowly, 
so that in 1889 Ebstein collected sixteen cases lastino; from five to 



230 SPECIAL PATHOLOGY OF THE BLOOD. 

twenty weeks, many of which appear to have been of the lymphatic 
variety. 

The knowledge of the chemistry of the blood has kept pace with 
that of the morphology. The first chemical analyses were those of 
Robertson, 1850 (January), and of Parkes, while a few months later 
Strecker examined the blood of a case of YogeFs. Later important 
contributions were made by Becquerel, Robin, and Scherer. In these 
early analyses the chief chemical alterations in the blood were fully 
indicated. The specific gravity of the blood was found as low as 
1.036 to 1.019, that of the serum 1.023 to 1.029. The iron was shown 
to be markedly diminished and the proportion of water increased, 
with a loss of albumins, especially of the red cells. Scherer reported 
the isolation of several organic acids in considerable traces, and of 
hypoxanthin, a body previously isolated from the spleen, while the 
presence of increased uric acid was demonstrated by both Scherer 
and Parkes, and later by Powlwarckzny, Koerner, and Mosler. 
The later chemical analyses of leukemic blood and tissue have 
been contributed by Stintzing and Gumprecht, Limbeck,^ v. 
Jaksch, Salkowski, Bockendahl and Landwehr, Freund and Ober- 
mayer. 

Etiology. Age. The histories of the earliest cases (Bennett) 
indicated that the disease may occur at almost any period of life. 
Later statistics showed that in the male sex the liability increases 
from childhood to the thirtieth or fortieth years, thereafter declining. 
In women most cases occur during active sexual life. In infants 
cases have been noted from birth, but the few cases recorded in 
childhood indicate that this period is comparatively immune. Audeod 
observed the disease in fifty-six children ; in the first year, eleven 
times ; two to four years, twelve times ; five to nine years, twelve 
times ; ten to fifteen years, twenty-one times ; the majority were 
boys. Of 135 cases collected by Ehrlich, Grawitz, Litten, 87 were 
males, 48 females. 

Heredity has figured in some remarkable cases, but its influence 
cannot usually be traced. Sanger observed a leukemic infant, born 
of a mother who was healthy and remained so. On the other hand, 
many leukemic women have given birth to healthy children. The 
influence of direct heredity is rare. Casati cited the case of a girl, 
aged ten years, whose father and grandmother were leukemic, while 
Cameron observed a case in a woman, whose grandmother, mother, 
brother, and two children were leukemic. Collateral heredity, the 
affection of brothers and sisters, has been frequently observed 
(;N"aunyn, Duret and Vaquez, Senator, Ortner, Casali, Greene, 
Eichhorst, Bernier). 

Trauma has been demonstrated to be a direct exciting cause of 
leukemia in a large number of authentic cases The traumatism 
has been applied directly to the spleen (Velpeau, Wallace, Mosler, 
Grawitz, Ebstein), or to the bones (Yirchow, Grawitz, Mursick), 
in which case the myelogenous type commonly develops. The 
traumatism may consist in general concussion. Pre-existing leukemia 
was thus rendered rapidly fatal in a case of Greime. 



LEUKEMIA. 231 

The significance of the alleged cases of leukemia foHowing splenec- 
tomy will be considered under that topic. 

Intestinal intoxication has been urged as the exciting cause of 
leukemia by A^ehsemever, who believes that the failure of conversion 
of peptone into harmless albumins of the blood is the important 
causal factor in the disease. This theory was suggested by the fre- 
quency of gastro-intestinal disturbances and lesions in leukemia, and 
by some observations of Kottnitz, which indicated that in leukemia 
the gastro-intestinal mucosa loses to some extent the power to trans- 
form peptones. 

The effects of bad hygiene have been traced in a large number of 
cases (Mosler), but no social position or occupation distinctly pre- 
disposes to the disease. 

Pregnancy appeared to be the predisposing or exciting condition in 
acute cases reported by Lauenberg, Stewart, Askanazy, Thompson 
and Ewing. 

Other diseases predisposing to or directly exciting leukemia have 
been reported as follows : 

Syphilis, acquired and constitutional, especially in children, and 
exciting usually the myelogenous type ; by Steinbrugge, Frankel, 
Hosier. 

Malaria, either acute or chronic (Miiller,^ Gowers, Osier), 33 per 
cent. Of 150 cases collected by Gowers, a history of previous 
malaria was obtained in 39, while in many the spleen had remained 
enlarged after the malarial attack. The disease has been attributed 
to diphtheria by Orth, and to typhoid fever, smallpox, and pneu- 
monia by Gowers. 

Influenza has several times been reported as leading to acute or 
chronic leukemia (Hinterberger, Frankel,^ Litten^). 

Rachitis, tuberculosis, and hypertrophic intestinal lymph follicles 
from chronic catarrh (constitutio lymphatica f) have been noted, singly 
or combined, in many cases in children (Hosier^). In a series of 
cases, both of myelemia and of lymphemia, extensive lesions of 
tuberculosis have been found. 

Stomatitis, ulceration of gums or tonsils, preceding or early accom- 
panying leukemia, have been reported by many observers (Ebstein, 
Hinterberger), but are probably secondary lesions. 

The transformation of pernicious anemia into leukemia has been 
reported in several cases (Waldstein, Litten,^ Masius and Fran- 
cotte, Leube and Fleischer, Musser). It does not appear, however, 
that any of these cases indicate a relation between progressive perni- 
cious anemia and leukemia. They seem to the writer to be cases of 
leukemia in which there was a temporary reduction in leucocytes at 
the time of first observation, or instances of marked terminal leuco- 
cytosis. The case of Masius and Francotte, in a patient suffering from 
ankylostomiasis indicates that severe secondary anemia may predis- 
pose to leukemia. An apparently genuine instance of transformation 
of pseudoleukemia into acute leukemia is reported by Mosler,^ and 
Troje has maintained that pseudoleukemia is pathologically a fore- 
runner of leukemia. This is a view of a large portion of the French 



232 SPECIAL PATHOLOGY OF THE BLOOD. 

school, but recent reports of such cases furnish, as a rule, unsatisfac- 
tory evidence that such transformations actually occur (cf. Wende, 
and Eosenfeld). 

The genuineness of many reported cases of leukemia following 
infectious diseases, splenectomy, childbirth, anemia, etc., has been 
seriously doubted, and it has been agreed on all hands that spurious 
cases have crept into the literature, especially before the general 
employment of Ehrlich's methods and criteria. The recent demon- 
stration of numerous myelocytes or lymphocytes in inflammatory 
leucocytosis (Engel, the writer, etc.), the extreme leucocytosis (1 to 2), 
observed by Schede and Stahl in osteomyelitis, and Musser's obser- 
vation of a proportion of one white to four red cells in pernicious 
anemia, render it obvious that the diagnosis of acute leukemia in the 
absence of microscopic examination of the marrow is often a hazard- 
ous undertaking. 

Infectious Origin. The chief ground for a belief in the infectious 
nature of leukemia is found in the rapidly fatal course of some acute 
cases and their striking clinical resemblance to other undoubted in- 
fectious diseases. Actual contagiousness is suggested by the report 
by Obrastzow, of an acute case developing in a hospital attendant six 
weeks after nursing another fatal acute case of the myelocytic type. 

Hintze and Frankel argue in favor of an infectious origin, and 
Askanazy, finding no leukemic lesions in a dead fetus from a leu- 
kemic mother, concluded that the disease is not excited by a circu- 
lating principle. 

Biological studies of leukemic blood have led to the reported 
demonstration of bacteria, and of other micro-organisms of unde- 
termined nature. Although no specific micro-organism has been 
demonstrated, it is not to be hastily concluded that some infectious 
agents are not concerned in the etiology of the disease, or that the 
micro-organism isolated in particular cases was not the direct excit- 
ing cause in those cases. 

It may very well be that the proliferation of leucocytes can be 
induced by various toxic agents, some of which are of bacterial origin. 

Bacteria. Kelsch and Vaillard squeezed drops of blood from the fingers, 
and isolated therefrom a diplobacillus which was pathogenic for mice. The 
same bacilli appeared in the vessels of the tumors. Pawlowsky claims to have 
found one and the same bacillus in six cases, sometimes in the blood, or in 
the viscera, especially in the liver. In the blood they were found mostly in 
the plasma. In cultures on glycerin agar the bacillus produced a somewhat 
characteristic growth. Injected into rabbits this micro-organism could be 
identified morphologically in the blood for several weeks, but no symptoms of 
leukemia were produced. Although Pawlowsky believes he has discovered a 
specific microbe in the disease, he has not yet verified his results. Bonardi 
obtained cultures of Staphylococcus pyogenes aureus and albus from the blood 
of two cases of splenic leukemia. 

Inoculations. Hosier and Westphal injected leukemic blood into dogs and 
rabbits with negative results. Bollinger with the blood, and Gilbert, Cadiot, 
and Eoger with the leukemic tissues of diseased dogs, failed to produce any 
significant effects by injections into healthy animals. 

The injection of leukemic blood and of the fresh juice of the spleen into 
various animals was without results in the hands of Mosler and Westphal, 
Bollinger, Nette, Eichenbush, and Miiller.* Nette injected defibrinated blood 



LEUKE^IIA, 233 

under the skin into the peritoneum, and into the veins of the ear, epigastrium, 
and marrow, with negative results. The juice of leukemic nodes was injected 
into animals without effect by Troje, Litten, and Gilbert. Negative cultures 
of blood were obtained in acute cases by Ebstein, Eoux, Westphal and Hosier, 
Outtmann, Mayet, Eichhorst,^ Pfeiffer, Litten, and Sittmann. 

Micro-organisms of undetermined nature have been described in the blood, 
or in the leucocytes, or in metastatic deposits, or in cultures, by Klebs,^ 
McGillavry, Osterwald, Mayet,- Roux, Bramwell, Fermi, and Klein. 

None of these writers has been able to follow up his observations. 

The observations of Mannaberg and of Lowit^ point to the pos- 
sible existence of protozoa in leukemic blood. 

In 8 per cent, of the lymphocytes of a case of lymphatic leukemia Manna- 
berg found hyaline bodies l,a to 4// in diameter, exhibiting ameboid activity 
such as is seen in the quartan malarial parasites. Thev failed to exhibit a 
nucleus by Romanowsky's stain, but after fixation in Hermann's fluid they 
stained well with safranin. 

In the peripheral blood and viscera in myelemia Lowit has described an 
ameba which he classes with the sporozoa and terms hemameba leukemice magna.. 
In lymphemia he finds another somewhat different ameba, hemameba leukemice 
vivax, which is scarce in the blood, but abundant in the viscera. In some 
mixed cases both amebse were present, and they were also seen in pseudo- 
leukemia and in v. Jaksch's anemia. Lowit has found the same amebse in 
leukemic animals, and claims to have transferred the disease from one animal 
to another. 

The method employed by Lowit in the demonstration of the parasite of 
leukemia is as follows : 

The blood smeared in a thin layer is heated one to two hours at 110° to 120° C, 
and stained one-half hour in a concentrated watery solution of thionin. After 
thorough washing in tap-water and drying in air, the specimen is laid for 
ten to twenty seconds in solution of iodine (f, 1 ; KI, 2 ; aq. dest., 300), again 
washed, dried, and mounted in balsam. The parasite in its various stages then 
appears green or olive-green, or greenish black, the basophile granules and 
degenerated products of nucleus and cell body bluish red or brownish red, 
the protoplasm of leucocytes and their granules yellowish or yellowish brown. 
The blood smear must be thin. The solution of thionin should be several 
weeks or months old, long exposed to sunlight, and preferably containing a 
considerable growth of micro-organisms which seem to assist in '* ripening" 
the stain. In the absence of an old solution good results may be obtained 
with a mixture of the thionin solution, 30 ; Loefiier's methylene blue, 15 ; but 
the green color of the parasites may be obscured by a diffuse dark stain from 
the methylene blue. The fading which ordinary preparations suffer within a 
few days may be avoided by mounting the specimen in balsam which has been 
mixed with a solution of iodine in xylol until the balsam is of light yellowish 
color. 

Lowit regards the greenish stain produced by his method as the specific 
reaction of the parasite, and finds reason to believe that this color is assumed 
by a substance identical with or closely related to cellulose. 

Turk believes that the hemameba of Lowit is an artifact resulting from the 
partial solution and deformation of mast-cell granules by the action of watery 
dyes, while others he regards as nucleoli of leucocytes. He claims to have found 
similar bodies in the blood of healthy men and rabbits and in the lymphocytes 
of chlorosis. His attempts to reproduce the disease in animals by injections 
of leukemic tissues were uniformly negative. Kraus, Widal, Hirschfeld and 
Tobias, Bloch, Litten, and Michaelis (cit. by Turk^) agree in general with the 
conclusions of Turk, while Vittadini, although finding the bodies only in leu- 
kemic blood, could not convince himself that they were parasitic. 

Pathological Changes in the Viscera. Only the portions of 
this extensive snbject will here be considered which bear upon the 
pathogenesis of the disease. 



234 SPECIAL PATHOLOGY OF THE BLOOD. 

Marrow. In the early stages of the leukemic process the lymphoid 
marrow exhibits a slightly lighter color and greater consistence than 
is normal. This change results from a cellular hyperplasia, which 
obliterates blood sinuses, diminishes the blood-content, and causes 
atrophy of fat cells. With this cellular hyperplasia of the marrow of 
ribs, vertebrae, etc., there is an extension of lymphoid marrow through- 
out the shafts of long bones, where also the marrow appears firm and 
light colored. AVhile in early stages the marrow may retain a fleshy 
tint, in advanced cases it is almost invariably very light colored and 
firm. In some advanced cases sclerotic and degenerative processes 
may follow the cellular hyperplasia, the writer having seen consider- 
able areas of connective tissue aud foci of mucoid degeneration in 
the marrow of old cases. In acute leukemia the marrow may be 
strikingly puriform in appearance, though invariably less diffluent 
than pus. In one case of the writer's this resemblance to pus was 
so marked as to require microscopic section before the true nature 
of the change could be positively identified. 

In myelocythemia the affection of the marrow has in all undoubted 
cases been distinct, and if Litten's case can be accepted, as is 
doubtful, the leukemic process may be limited to the marrow. 
Leube and Fleischer (1881), Eichhorst, and recently Ambros, Hirsch- 
laff, Kormoczi, and Denning have attempted to show that the lesion 
in the marrow may be absent in lymphemia, but their cases seem to 
have been examples of marked terminal lymphocytosis, probably in 
pernicious anemia. In lymphatic leukemia it was early shown that 
the marrow may be very slightly involved (Heuck,^ Fleischer, Pen- 
zoldt), but in most cases the usual extensive hyperplasia is observed 
and in some reported cases of lymphemia the lymphoid hyperplasia 
was almost exclusively limited to the marrow (Kormoczi, Walz 
Pappenheim, Hirschlaff, and Peed). 

Neumann and Pappenheim'^ claim that lymphatic leukemia is always of 
myelogenous origin, and the latter observer suggests that if the lymphoid hyper- 
plasia affects first or only the spleen or lymph nodes pseudoleukemia results, 
while in lymphemia the lymph nodes and spleen are only secondarily involved. 
This view is apparently disproved by Rosenfeld's case of lymphemia in which 
no change was discovered in the marrow, while the spleen and lymph nodes 
were greatly enlarged. 

The early and extreme involvement of the lymph nodes and spleen in many 
cases is also strong presumptive evidence against such a view. 

The microscopic examination of the marrow in leukemia shows that 
the hyperplasia affects the variety of cells seen most abundantly in 
the blood. In myelocythemia these cells are largely the neutrophile 
myelocytes, which are found in very excessive numbers, of very 
large size, and in mitotic division or in various stages of degenera- 
tion. In the same cases, also, there is almost invariably an excessive 
number of large mononuclear hyaline cells. Eosinophile and giant 
cells may long persist, but do not appear to take a prominent part in 
the hyperplasia. 

In pure lymphatic leukemia the lymphocytes alone are found in 
the hyperplastic areas (Miiller^) and eosinophile and neutrophile cells 
are very scarce. 



LEUKEMIA. 235 

It is held by some (Ponfick, Mosler,^ Miiller^) that the leukemic process may 
at one period of its course affect principally the lymphoid structures, at an- 
other the marrow, so that the blood may at one time exhibit the changes of 
lymphatic, at another those of myelogenous leukemia. Fleischer and Pen- 
zoldt's case illustrates such a variation, and Michaelis has described another 
with the same purport. 

Recent studies of leukemia have failed to support this view, which is strongly 
contradicted by the nature of the lesions which involve a hyperplasia of par- 
ticular cells. 

The red blood cells of the marrow are not greatly affected in the 
early stages of leukemia, as is indicated by the frequent absence of 
marked anemia, although in very cellular areas they are diminished 
in number from the first. Later in chronic myelogenous cases the 
same changes are seen as in pernicious anemia, but the excessive 
numbers of megaloblasts are seldom so prominent. In some acute 
cases, especially those of lymphatic type, the writer has seen almost 
entire absence of nucleated red cells in considerable sections. 

The distribution of the lesion in the marrow of lymphatic leukemia 
is often very irregular. In an acute case the writer has found 
entirely normal structures in the ribs and femur, while the usual 
hyperplasia was present in the bodies of vertebrae. Moreover, the 
lesion, at least in its early stages, appears to be focal rather than 
diffuse. These peculiarities render it essential that very complete 
examinations should be made before it can be positively claimed that 
leukemia can exist without lesions in the marrow. 

Liver. The enlargement of this organ is usually referable to the 
presence of numerous metastatic growths which follow the course of 
development described for all secondary leukemic deposits, and to 
infiltration of capillaries with proliferating leucocytes. In myelo- 
cythemia the liver is seldom free from such deposits, but in the 
lymphatic type the infiltration is usually limited to the portal canals 
and intralobular capillaries, although it may produce circumscribed 
tumors. 

It is of great interest to note that the liver in myelocythemia gives 
evidence of having resumed its embryonal function of developing 
red cells. Neumann and Heuck first called attention to the presence 
of considerable numbers of nucleated red cells in the hepatic capil- 
laries. In Heuck's case they were distinctly more abundant than 
in the general circulation. The resemblance of the leukemic to the 
embryonal liver is completed in the presence of mitotic leucocytes 
and giant cells, as described by Neumann,* Miiller, Michaelis, and 
others. 

Spleen. The pathological process in the spleen consists in hyper- 
plasia of large and small mononuclear cells. These cells appear in 
excessive numbers throughout the pulp cords, while the limits of the 
Malpighian bodies become less defined. As a result of this cellular 
hyperplasia, the sinuses are choked with cells, and hemorrhages, 
infarcts, degeneration, and necroses occur, which lead to a variety of 
gross appearances in the enlarged organ. 

Regarding the exact nature of the cellular processes, it has been 
shown that in myelocythemia, while the majority of the cells in the 



236 SPECIAL PATHOLOGY OF THE BLOOD. 

spleen are hyaline, yet neutrophile myelocytes occur in moderate 
numbers. These are generally regarded as deriyatiyes pf the marrow 
brought by the blood stream, although Miiller has once seen mitosis 
in a splenic myelocyte. Numerous giant cells are sometimes found, 
\yhich Miiller regards as originating in situ. For the increased 
number of large and small lymphocytes, the chief mode of origin 
must be mitotic or amitotic division in situ, especially in the Mal- 
pighian bodies, as has been demonstrated by Miiller. Along with 
this excess of colorless cells the organ commonly contains an excess 
of blood, and the usual process of destruction of red cells may eyery- 
where be observed. 

Nucleated red cells are visible in smears of splenic pulp in most 
cases of myelocythemia. The writer has been unable to conyince 
himself that they are more numerous than in the general circulation, 
or, if slightly more numerous, that they are not mechanically 
sifted from the blood. Heuck, however, found them in the splenic 
smears when they were absent in the general circulation, and concluded 
that the spleen in leukemia may resume its embryonal function of 
developing red cells. 

Following the stages of acute hyperplasia comes a later period 
marked by continuous increase in the size of the organ and great 
increase in consistency, owing to fibroid changes beginning in the 
trabecula and often extending diffusely throughout the pulp. In 
such stages the cellular-content is comparatively diminished without 
any apparent effect upon the character of the blood. 

In lymphatic leukemia the same course of events is observed, but 
the new cells are limited to the large and small lymphocytes. In this 
form of the disease the lymph follicles are apt to be enlarged. 

The general appearance of sections of the spleen in myelocythemia, 
the congestion, the indiscriminate filling of sinuses with red and 
white cells, the destruction of Malpighian bodies, the prominence of 
fibroid changes, and the usual absence of areas of distinct leukemic 
deposits, strongly indicate that the enlargement of this organ results 
largely from mechanical sifting of red and ivhite cells from the circu- 
lation and subsequent inflammatory changes. In lymphatic leukemia, 
however, the proliferation of lymphocytes is usually very marked, 
and the Malpighian bodies mnst be considered one of the most 
important primary seats of the disease. In some cases it may, per- 
haps, be the exclusive seat of the primary lesion (cf. Hirschlaff, 
Rosenfeld). 

Lymph Nodes and Other Lymphatic Structures. Swelling of the 
lymph nodes is one of the earliest of observed symptoms, having in 
some lymphatic cases preceded all other signs for some months. 
They may reach a considerable size, that of a hen's egg, but seldom 
become excessively large. Their capsules are almost invariably 
intact, unless ulceration occurs. The stage of cellular hyperplasia is 
succeeded, here as in the spleen, by one of fibrosis with diminution 
in the number of cells. 

In myelocythemia the smears of lymph nodes yield almost the 
same appearances as those of the spleen, except for a relative excess 



LEUKEMIA. 237 

of lymphocytes. Xeutropliile myelocytes are scanty, but here again 
Miiiler has found mitosis in myelocytes. On section the outlines of 
the lymph follicles are lost, and the tissue consists of a diffuse mass 
of mononuclear cells, large and small, resembling lymphocytes, and 
often seen in mitotic diyision. In some cases distinct proliferation 
zones appear in small foci where the multiplication of leucocytes is 
very actiye. 

Although the sinuses are usually choked and indistinguishable, yet, 
according to Birch-Hirschfeld, most of the lymph nodes of leuhemia 
differ from those of pseudoleul-emia, in the fad that substances injected 
into the capsules pass through the leukemic node into the efferent vessel, 
but in p)seudoleuke)nia the enlarged nodes are impervious. The writer 
has been unable to find, in the literature or in sections and smears of 
nodes from his own cases, any constant microscopic differences dis- 
tinguishing the lymph nodes of the lymphatic from those of the 
myelogenous type of the disease. In the former the small lympho- 
cytes are rather more numerous, and, of course, the hyperplasia is 
usually much more marked. 

In addition to the lymph nodes, spleen, and marrow, all pre- 
existing lymphoid structures may become hyperplastic, especially in 
lymphatic leukemia, and new-growths of lymphoid tissue have been 
found of nearly universal distribution. From all of these localities 
new leucocytes are undoubtedly contributed to the circulation. 

Character of Metastatic Deposits. Although Eindfleisch, Cornil 
and Ranvier, and Zeigler, held that leukemic deposits arise by 
mechanical lodgement of increasing numbers of leucocytes from the 
blood, Yirchow early maintained that these deposits arise in situ. It 
has since been shown that while the early minute collections of cells 
are white cell thrombi, the further growth of these masses takes place 
principally by mitotic division of these cells (Bizzozero, Miiiler, and 
Neumann). Bizzozero has pointed out that the structure of these 
metastases closely resembles that of lymph nodes with reticulum and 
sinuses, and is not at all that of an indiscriminate deposit of blood 
cells. He found in such deposits quite as many mitotic nuclei as in 
similar nodules of metastatic carcinoma. Leukemic deposits must,, 
therefore, be regarded as conforming in many important respects to 
the laws governing metastatic neoplasms. 

The lymph nodes and spleen when affected exhibit a hyperplasia 
of the lymphocytes, which choke the sinuses, obliterate the follicles,^ 
and cause an overflow of these cells into the blood and probably also 
into the lymph stream. In lymphatic leukemia the new cells are of 
small size ; in myelemia the cells are either of small size or larger, 
and with a distinct mass of protoplasm about the nuclei. The writer 
has made several attempts to demonstrate neutrophile granules in 
the cells of the lymph nodes in myelocythemia, but without success. 
In chronic cases the stage of hyperplasia is regularly followed by 
one of fibrosis, which in the spleen greatl}^ increases the size and 
consistence of the organ. 

Pathogenesis. The conclusions regarding the pathogenesis of 
leukemia which seem to be warranted from the foregoing review of 



238 SPECIAL PATHOLOGY OF THE BLOOD. 

the etiology and pathological anatomy of the disease are, to a large 
extent, those formulated by Virchow and Xeumann, whose original 
ideas have been partially readjusted from time to time to suit newly 
acquired facts. 

Leukemia must now be considered a primary disease of tlie blood-- 
producing organs. The essential process consists in an excessive 
hyperplasia of the myelocytes or lymphocytes, with secondary increase 
of leucocytes in the blood, secondary lesions in the blood-forming 
and other organs, and leading eventually to disturbances in the pro- 
duction of red cells and to pernicious anemia. In the myelocytic 
type, the marrow and the neutrophile myelocytes are involved, and 
the development of red cells is soon disturbed, probably by mechan- 
ical conditions, possibly also by disturbance of the normal differen- 
tiation of the primitive parent cell into red cells. In lymphatic 
leukemia the lymphoid structures (lymph nodes, spleen, lymph cells 
of marrow) are almost exclusively affected, and red-cell formation 
is less early disturbed. It appears that lymphemia may principally 
affect one organ (the marrow) at one time, and another organ (the 
lymph nodes) at a later stage. In lymphatic leukemia the spleen 
may take active part in the initial process and furnish many new 
lymphocytes to the blood, but in myelocythemia its behavior is 
largely passive, and it seldom becomes the seat of true leukemic new- 
growths, but may as usual furnish lymphocytes to the blood. 

The attempts to explain the various alterations in the leucocytes in leukemia 
and the numerous changes which the cell types in the disease undergo, by ref- 
erence to the theory that a primitive parent cell exists in the marrow and domi- 
nates these changes has not, in the writer's opinion, been very successful. 

It does not appear that the existence of two very distinct types of the disease 
has been rendered in any serious degree uncertain. Several observers have 
claimed that while in chronic leukemia the more differentiated types of white 
cells, lymphocytes and myelocytes, are produced in excess, in acute leukemia 
it is the parent lymphocyte itself which is multiplied. 

It is claimed also that the transformation of chronic leukemia of either 
type into acute is marked by a disappearance of the more differentiated cells and 
the appearance of the earlier primitive lymphocyte (Frankel, Wey), and that 
in acute leukemia we have a point of union of the leukemic types. 

This conception, while favored by many important theoretical considerations, 
is still largely conjecture unsupported as yet by definite observations. There 
are as yet no morphological criteria on which to identify the primitive lympho- 
cyte, nor is the normal location of this cell clearly determined. It may be 
true that cases of acute leukemia exist in which the primitive parent cell 
appears in excess, but the morphology of the large cells in acute leukemia 
indicates that in the great majority of cases these large cells still fall into two 
rather distinct classes, viz., large hyaline or basophile mononuclear cells with- 
out a trace of granules, and large myelocytes, more or less deficient in gran- 
ules. In myelocythemia the cells are considerably removed from the parent 
cell, and the deficiency of granules is most reasonably referred to the degen- 
erative changes associated with rapid multiplication. 

In lymphemia the morphology of the cells oscillates between that of distinct 
lymphocytes and that of the larger, pale, hyaline cells, derived from marrow, 
spleen, and lymph nodes, for which no one can claim a capacity to develop 
into any other cell than the differentiated lymphocytes. 

It thus appears most probable that the hyperplasia of leukemia affects certain 
derivatives of the parent lymphocytes which may closely approach each other 
in morphology, but that the separation of two types of leukemia always 
remains distinct. The relation of a primitive parent cell to leukemia remains 



LEUKEMIA. 239 

for future observations to determine, and this can probably not be successfully 
accomplished by theoretical deductions, as some have attempted to do, but 
only by actual study of the concrete facts presented by the disease. 

The importance of proliferation of leucocytes in the circulation has 
been maintained, especially by Biesiaclecki and Lowit/ who believe 
that lenkemia is a primary disease of the blood. While nearly all 
experienced observers agree that leucocytes multiply to some extent 
in the circulation, there is almost equal agreement that tlue extent of 
mitotic division in the blood is inconsiderable compared with that in 
the viscera. 

The leukemic deposits of the viscera develop by proliferation of 
original thrombi of leucocyteSj wliich under favorable conditions 
undergo active mitotic division, develop a supporting stroma, and 
behave in essential particulars like true neoplasms, while probably 
continuing to furnish new leucocytes to the blood. 

The red cells during the early stages of myelemia suffer from the 
disturbances of development, such as exist in chlorosis. In later 
stages red-cell production reverts to the embryonal megaloblastic type, 
mitotic megaloblasts are seen in the marrow, spleen, and liver, and 
the changes of pernicious anemia are established in the blood. 

The partial resemblance of leukemia to a neoplasm affecting the 
lymph nodes, spleen, marrow, or blood was early recognized, and 
this theory of origin has been discussed by most writers and openly 
maintained by Kottman, Bard, Herzfeld, and lately by Gilbert, who 
compares lymphemia to a sarcoma affecting lymphocytes. 

To what extent the origin and course of leukemia follows the 
laws known to govern neoplasms is an interesting inquiry, which 
■cannot here be pursued at length, but which may well be kept in 
mind. According to such a theory it is necessary to suppose that 
lymphatic leukemia is a tumor originating in the lymphocytes, 
myelemia a tumor affecting myelocytes. 

There are, however, other tumors affecting lymphocytes, the 
lymphosarcomata, which behave in a very different manner from 
lymphemia in growth, and especially in their metastatic characters. 
The cases of lymphemia arising in the course of lymphosarcoma are 
here of great interest (Palma). Leukemia has also been found asso- 
ciated with carcinoma (Lannois and Regaud), and with endothelioma 
of lymph nodes in a lymphatic case studied by the writer. 

Changes in the Blood. 

The bulk of blood is apparently little altered by the uncomplicated 
leukemic process, but in autopsies on chronic cases the same diminu- 
tion in the total quantity of blood may be noted as in pernicious 
anemia, and from the same cause. 

The color of the blood may in well-marked cases be entirely 
normal, as anemia is of slow progress. Usually it is slightly lighter 
in color and more fluid, owing to pronounced anemia and great excess 
of leucocytes. The exuded drop has been described as lymphoid or 
puriform, but when properly expressed blood of such character must 



240 SPECIAL PATHOLOGY OF THE BLOOD. 

be extremely rare. When the red cells are below 1,000,000, and the 
leucocytes almost equally numerous, the blood drop still resembles 
blood, though of very light color. When obtained in bulk at autopsy 
the blood coagulates slowly, the red cells settle to the bottom, fol- 
lowed by a characteristic thick layer of leucocytes and fibrin, while 
the very clear serum floats above. In the cadaver deposits of leuco- 
cytes resembling abscesses may be found in various situations, often 
in the heart and pulmonary vessels. 

The coagulability is greatly diminished and may be entirely lost, 
but less often than in fatal pernicious anemia. 

To the touch the blood may have a cohesive mucous quality, as 
noted by Grawitz. 

When leukemic blood is smeared and dried on a glass slide, it 
exhibits a peculiar granular opaque appearance which is readily 
identified as belonging to a great excess of leucocytes. 

The Red Cells. In average chronic cases the red cells are usually 
reduced to 2,000,000 to 3,000,000, falling to 1,000,000 or lower in 
fatal cases, but not usually reaching the extreme reductions seen in 
pernicious anemia. On the other hand, Cabot reports a case with 
over 5,000,000 red cells, 134,000 white, Hb 78 per cent. At death 
the numbers of red cells depend upon the presence or absence of 
hemorrhage, and upon the length and character of the disease. 
There are no marked differences in the grade of anemia in lympho- 
cytic and myelocytic leukemia. 

Morphological changes in the red cells are invariably present. In 
the average chronic case the uniform loss of Hb in red cells showing 
normal rouleaux and very uniform size and shape, with a rather free 
admixture of normoblasts, gives to the stained blood smear a very 
peculiar and almost pathognomonic character. Possibly the abun- 
dance of leucocytes controls the movements of the red cells in the 
smearing process, but from some cause the appearance of the red cells 
in stained specimens of leukemic blood is very characteristic. (See 
Plate VIII.) At this early stage the normoblasts are frequently 
present in greater numbers than in any other similar condition. 

Later the red cells begin to show the changes of more severe 
chlorotic anemia, differences in size and shape appearing, degenera- 
tive changes occurring with greater frequency and extent, until in 
many old severe cases the features of pernicious anemia are fully 
established. Even in such stages, however, the appearance of the 
red cells usually differs distinctly from that of pernicious anemia in 
the more uniform loss of Hb and in the larger number of nucleated 
red cells, among which a few are almost invariably normoblasts. 
Mitotic nucleated red cells are rare. In most other respects the same 
changes are seen as in pernicious anemia. 

Hemoglobin. Estimates of Hb in leukemia are at present some- 
what unsatisfactory, owing to the opacity produced in the diluted 
blood by an excess of leucocytes. In the early stages of the disease 
the loss of Hb follows the reduction in red cells, as in chlorosis, a 
diminution being demonstrable at times before any change in the 
number of red cells, and the Hb-index remaining about 0.5 to 0.6: 



PLATE VIII. 










.*^^i5v^ 






* »• 



1^ 



•:A-::/*V 



10 



w 



Vh \\:.' - . 



Myelogenous Leukemia. Triacid Stain. 



Figs. 1. Normal-sized red cells deficient in Hb. 

Figs. 2. Pear-shaped poikilocyte. 

Fig. 3. Normoblast. 

Fig. 4. Myelocytes (Ehrlich's). 

Fig. 5. Myelocyte (Cornil's). 

Fig. 6. Myelocyte (eosinopliile) . 

Fig. 7. Eosinophile leucocyte (normal). 

Fig. 8. Blood plates. 

Fig. 9. Lymphocyte. 

I'^ig. 10. Polynnclear leucocyte, nucleus subilivided. 



LEUKEMIA. 241 

Later the estimates are untrustworthy^ but the Hb-index probably 
rises. 

The Leucocytes. The white cells are usually so much increased 
as to leave no doubt, from their numbers alone, as to the nature of the 
disease. In cases of very moderate severity there are usually from 
100,000 to 200,000 leucocytes ; Cabot^s average of first examinations 
in 39 cases was 438,000. Rarely 1,000,000 or uiore white cells are 
present in the cubic millimetre of expressed blood, but it appears 
doubtful if any such excessive number actually exists throughout 
the circulation. 

As a rule, the severity of the general condition is proportionate to 
the increase of leucocytes, except in acute leukemia, when the number 
of leucocytes may not exceed that of inflammatory leucocytosis. 

Variations in the number of leucocytes may be observed at differ- 
ent periods of the day, as shown by Hayem, who found 1 22,500 at 
10 A.M., and 235,000 at 4 p.m. of the same day. These rapid changes 
must be referred largely to vasomotor disturbances leading to unequal 
distribution of cells, or, possibly, to a sudden but temporary increase 
of the leucocytes discharged from the marrow. Other variations in 
number of leucocytes will be considered under the course of the 
disease. 

Morphology of Leucocytes in Myelemia. 1. Neuteophile Myelo- 
cytes. These are large mononuclear cells with neutrophile granules. 
It is of some moment to distinguish two varieties of neutrophile 
myelocytes in leukemia. 

(a) Cells of about the same size as normal polynuclear leucocytes, 
with well-staining, central nucleus, as described by Ehrlich and 
Utheman. These cells are abundantly present in leukemic blood 
and are generally the only form of myelocyte seen in secondary anemia. 
(Plate VIIL, Fig. 4.) 

(6) Cornil and H. F. Miiller have called special attention to the 
large myelocyte with pale eccentric nucleus. This cell is not usually 
seen except in leukemia, but in some other conditions, especially in 
the secondary anemia of children, it may appear in moderate numbers. 
These cells have frequently been seen in mitotic division. (Plate 
VIII., Fig. 5.) 

As first shown by Hosier, and abundantly verified by later 
observers, the presence of large numbers of neutrophile myelocytes 
is pathognomonic of leukemia. In 28 cases (chronic ?) Cabot found 
that between 20 to 60 per cent, (average 35 per cent.) of all leuco- 
cytes present were myelocytes. With the extreme leucocytosis of 
chronic leukemia there are nearly always enough myelocytes present 
to establish the diagnosis as against any other condition that has yet 
been observed. 

In acute myelocytic leukemia, hoivever, this rule may fail and both 
the numbers and proportions of myelocytes may not exceed those seen by 
JEngel in fatal diphtheria. 

Of recent cases of acute leukemia in which the type of the disease was satis- 
factorily determined, Frankel (1895) could find only three of myelocytic type, 
the great majority being of the lymphatic variety. In 1897 the writer saw 

16 



242 SPECIAL PATHOLOGY OF THE BLOOD. 

three cases of rapidly fatal leukemia, verified by autopsies, and all of the mye- 
locytic type. They occurred in the services of Drs. Thomson and Delafield, 
at Eoosevelt Hospital, In two of these the changes in the blood were from 
the first observation typical of the condition and the marrow was puriform, 
while the spleen and lymph nodes were but slightly affected. In the third 
case, on the first examination, with a leucocytosis of ordinary inflammatory 
grade, 5 per cent, of the cells were with difficulty recognized as myelocytes. 
Eosinophil e myelocytes and normoblasts were absent, and there was then not 
sufficient ground on which the diagnosis of leukemia could rest. Later, the 
leucocytosis and the proportion of myelocytes increased and the diagnosis of 
acute leukemia, made with reserve just before death, was fully verified at 
autopsy. 

In this case, on account of the small numbers and indistinctness of the 
granules in the myelocytes, as well as the moderate grade of leucocytosis, the 
writer did not feel certain of the diagnosis until after the microscopic exam- 
ination of the bone-marrow. 

Degenerative Changes in Myelocytes. The myelocytes of leukemia 
are usually deficient, and ma.y he entirely lacking, in neutrophile 
granules. In the latter case they are indistinguishable from large 
lymphocytes, except by the great pallor of their nuclei (triacid 
stain). Such forms occur especially in acute leukemia. The nuclei 
of degenerating myelocytes may undergo hydropic degeneration. It 
is then practically impossible to determine the origin of these altered 
cells. (Plate X., Figs. 1 and 2.) Some very small mononuclear cells 
with neutrophile granules seen in leukemic blood Ehrlich regards 
as the result of subdivision of polynuclear leucocytes (neutrophile 
pseudoly mphocy tes) . 

2. Polynuclear neutrophile leucocytes are excessively 
numerous in myelocythemia, but are commonly found in diminish- 
ing proportions, though in increasing numbers, as the percentage of 
myelocytes increases. Cabot, using the triacid stain, found between 
17 and 72 per cent, (average 46 per cent.) of polynuclear leucocytes. 
Even when the myelocytes are relatively few their presence seems 
always to be at the expense of polynuclear cells, a fact which indi- 
cates a slower progress to full development as well as increased 
production of these cells in the marrow. The most successful demon- 
stration of nuclear figures in these cells (e. g., by Nocht's stain) 
show very numerous transitional forms between the spheroidal and the 
multilobate nucleus, while after the triacid stain it is usually impos- 
sible to distinguish between many single and polymorphous nuclei in 
neutrophile cells. 

In lymphatic leukemia polynuclear leucocytes are usually scarce 
and may not be found at all. 

Degenerative changes in the polynuclear leucocytes are very common 
and very marked. Their cohesiveness is increased and they appear 
in large inseparable groups with myelocytes Their nuclei are usually 
pale (karyolysis) and may become excessively faint. Gumprecht 
suggests that this pallor of the nuclei of neutrophile cells indicates 
the transformation of the nucleins into xanthin bodies ; or the lobes 
may become more numerous, entirely separate, very compact, and 
densely staining (pyknomorphous), while the granular cytoplasm is 
replaced by homogeneous, highly refractive material (Plate X., Figs. 



PLATE X. 




Degenerating Leucocytes in Myelogenous Leukemia. 
(Triaeid Stain. ) 



Fig. 1. Myelocj'ie deficient in neutrophile granules. 

Fig. 2. Necrotic myelocyte, complete karyolysis; hydropic degeneration; loss of ne\itrophile 

granules. 
Fig. 3. Degenerating myelocyte. Hydrops of nucleus. 

Fig. 4. Polynuclear leucocyte deficient in neutrophile granules: hydrops of nucleus. 
Figs. 5, 6. Polynuclear leucocytes. Loss of neutrophile granules. Advanced subdi\'ision of 

nucleus. 
Fig. 7. Myelocyte in mitotic division. (Eosin and methylene blue.) 
P"'ig. 8. Eosinophile leucocyte. Some granules basophilic. (Eosin and methylene blue.') 



LEUKEMIA. 243 

5 and 6) ; or the nuclei may undergo hydropic degeneration. (Plate 
X.^ Fig. 4.) All grades of deficiency of granules may be observed, 
but the writer has been unable to demonstrate fat in the neutrophile 
cells of leukemia. Considerable variations in the size of these cells 
may be noted in some cases of leukemia. 

3. EosiNOPHiLE CELLS are usually much increased in number in 
myelocythemia, but their proportions to other forms of leucocytes 
commonly vary within normal limits. In some cases, however, the 
proportions are increased, but never so much as in cases of pem- 
phigus, etc. Their proportions are not pathognomonic of the disease, 
but in most cases their total numbers greatly exceed those found in any 
other condition. Ehrlich places their numbers between 3,000 to 
100,000 per c.mm., thereby practically demonstrating, as he originally 
claimed, that the excess of eosinophiles is among the pathognomonic 
signs of the disease. In some specimens of blood the eosinophile 
cells vary greatly in size, some of them being very small, while 
their neighbors are hypertrophic. A few large basophilic granules 
may be found in the polynuclear as in the mononuclear eosiuophiles 
of leukemia. These cells are actively ameboid. 

In acute leukemia of both types and in chronic lymphocythemia 
eosinophiles are scarce or absent. 

Eosinophile myelocytes are mononuclear cells with eosinophile 
granules. 

In some of these cells the granules are of uniform size and staining 
quality, or there may be some basophile granules among the eosino- 
phile, or the granules may vary greatly in size and in density of 
stain. Eosinophile myelocytes with granules of very unequal size and 
density of stain are, in the writer^ s experience, pathognomonic of myelo- 
cythemia. (Plate YIII., Fig. 6.) Bignami, however, speaks of the 
occurrence in pernicious malaria of eosinophile myelocytes '^ such as 
are seen in leukemia." 

In the majority of cases of myelocythemia eosinophile myelocytes 
constitute a large proportion of all eosinophile cells present. In 
lymphatic leukemia they are almost always absent, and in acute 
leukemia they are scarce or absent. 

4. Lymphocytes. The numbers and proportions of lymphocytes 
in myelocythemia vary in different cases and at different periods in 
the same case, and one must be prepared to find marked variations in 
the proportions of lymphocytes without being able to attach much 
significance to such changes. As a rule, the lymphocytes are much 
increased in numbers, while diminished in relative proportions to the 
neutrophile cells. The increase of lymphocytes appears to have no 
uniform relationship to the stage or character of the disease, as small 
numbers are found at early stages of some cases, and large numbers 
in the late stages of others, and vice versa. Cabot found an average 
of 10.6 per cent., but when at their lowest (2 per cent.) they were 
still more numerous than in normal blood. The proportions of 
large and small lymphocytes also vary without apparent relation to 
the other features of the disease. Usually but not always the large 
cells outnumber the small. It is probable that many myelocytes 



244 SPECIAL PATHOLOGY OF THE BLOOD. 

deficient in neutrophile granules are commonly enumerated among 
large lymphocytes, especially in acute myelocythemia. Turk's 
^^ Reizungsformen/' mononuclear cells with opaque, densely staining 
cytoplasm, are also commonly included among the large lymphocytes. 
They are probably ancestral forms of megaloblasts. The access to 
the blood stream in myelocythemia of large numbers of true lympho- 
cytes, small and large, may be referred to a secondary, but, neverthe- 
less, continuous hyperplasia of these cells in the marrow and lymphoid 
tissues, and to accidental and temporary factors which excite their 
proliferation and attract them to the blood. Their presence, even 
in considerable numbers, cannot at present be regarded as an indica- 
tion that the disease is of mixed type. 

5. Laege mononuclear leucocytes, with very faint cytoretic- 
ulum and vesicular nucleus, are seen in considerable numbers in 
most cases of leukemia, but they appear to lack special significance. 
They are very apt to suifer damage in the smearing process and to 
appear in the dry specimen as large, coarsely reticular nuclei, without 
demonstrable cell body. (Plate IX., Fig. 3.) These cells may con- 
tain granules giving the reaction of glycogen. The larger forms 
may show horseshoe-shaped nuclei. In the cases of acute leukemia 
described by Frankel and others, the majority of cells were large 
mononuclear leucocytes. 

Degenerative changes are noted in the small and often in the large 
lymphocytes of leukemia. The nuclei of the small cells, instead of 
remaining compact, may become incurved and finally bilobed or 
trilobed, while the cell body remains basophilic (Rieder, Ehrlich). 
Litten^ describes, in two acute cases, very large cells in which the 
nucleus was obscured by many globules of fat blackened by osmic 
acid. There are some other reports of fatty degeneration of leuco- 
cytes in leukemia, but apparently none from very recent literature. 
Mitotic figures in lymphocytes of lymphemia are reported by 
Wertheim. 

6. Mast-cells. These cells are very constantly increased in chronic 
myelocythemia, but in some cases a prolonged search is required for 
their discovery. Although occasionally seen in other conditions, in 
leukemia they are usually so markedly increased as to constitute a 
very reliable diagnostic feature of the blood. They are at times more 
abundant than the eosinophile cells. They are usually absent in 
lymphemia, and the writer has failed to find them in acute myelo- 
cythemia. 

Strauss found 5 per cent, of mast-cells among the leucocytes in 
blister fluid from a case of myelocytic leukemia, and Milchner 
reports 23.9 per cent, of mast-cells in the sediment from ascitic 
fluid in a similar case. In the blood of one case Taylor reports the 
remarkable number of 140,000 mast-cells. 

Special Characters of the Blood of Lymphatic Leukemia. In 
this type of the disease the lymphocytes are the only form of white 
cell appearing in the blood in increased numbers. In cases in which 
a positive clinical diagnosis is possible, the nature of the condition is 
at once evident from the great abundance of these cells, but owing to 



PLATE IX. 




Lymphatic Leukemia. (Eosin and Methylene Bhie.) 



Figs. 1. Small lymphocytes. 

Figs. 2. Medium.-sized and large lymphocytes. 

Fig. 3. Degenerating basket-shaped miclevis of large lymphocyte, witliout cytoplasm. 

Fig. 4. Polynuclear leucocyte. Nodal points of cytoreticuhnn. 

Fig. 5. Red cell. Polychromasia of Maraghano. 



LEUKEMIA. 246 

the numerous other causes of chronic lymphocytosis it is at present 
impossible to state what is the lowest proportion of such cells seen in 
the blood of genuine lymphemia. In well-marked cases they are 
quite as numerous as the leucocytes of myelocythemia, while some 
of the highest counts on record have been reported in this type of 
the disease. 

Usually the lymphocytes are of small size and normal structure, 
and the writer has specimens of one very marked case, in which 
almost all the leucocytes were small mononuclears. Their percent- 
age commonly runs between 80 and 90. 

In rather rare cases reported by Frankel, Grawitz, Cabot, and 
others, and in one child observed by the writer, the great majority 
of the cells were unusually large and their cytoreticulum faintly 
staining. Between the two extremes are cases showing various pro- 
portions of small, medium-sized, and large lymphocytes. The small 
lymphocytes are usually more abundant in chronic cases and in 
adults, the larger cells tending to become prominent in acute cases 
and in children. Gerhardt refers to a case in which large lympho- 
cytes, abundant in the early acute stage, were replaced during a 
chronic course of six months, by small lymphocytes. 

Frankel believed that these cells could be regarded as pathognomonic of 
acute lymphatic leukemia, but his claims have been fully disproved. Large 
mononuclear cells with hyaline bodies were common in the writer's cases of 
acute myelocythemia, and reasons have been given to show that some of these 
cells may result from loss of neutrophile granules of myelocytes. Askanazy 
insists that the large cells of Frankel are not lymphocytes, but myelocytes 
deficient in granules, a view to which the writer is inclined from the study of 
three cases of acute leukemia. Hirschlaff has recently reported two acute cases 
in which most of the leucocytes were large mononuclear cells without granules. 
In a moderate proportion of them neutrophile granules and in a larger number 
eosinophile granules were noted. 

This variation in size of lymphocytes may have an anatomical basis in the 
structure of the hyperplastic lymph nodes, as in some cases these nodes con- 
tain mostly small lymphocytes, at other times large mononuclear cells. 
(Birch-Hirschfeld, Benda ) 

These and other considerations oppose the interesting view recently ex- 
pressed by Rosenfeld, that when the lesion of lymphemia is in the marrow 
many large lymphocytes appear in the blood, anemia rapidly develops, and 
the disease runs a severe course, while if the lesion affects only spleen and 
lymph nodes large lymphocytes are absent from the blood and anemia is of 
slow development. 

Myelocytes, both neutrophile and eosinophile, and mast-cells are 
usually absent or extremely scarce in lymphemia, but are occasionally 
seen in scant numbers (Miiller). Polynuclear leucocytes, both neu- 
trophile and eosinophile, are also comparatively scarce. 

The red cells suffer the same changes as are seen in myelocy- 
themia, but nucleated red cells are usually very scanty and may not 
be found at all. Da Costa, however, found 10,678 nucleated red cells 
in one case, the great majority normoblasts. 

Variations in the Blood Changes in Leukemia. Both the 
numbers and the proportions of leucocytes in leukemia are subject 
to considerable variations from manv causes. 



246 SPECIAL PATHOLOGY OF THE BLOOD. 

1. Intercurrent Diseases. A considerable Dumber of cases have been 
reported sho\Ying that intercurrent infections may greatly alter the 
appearance of the blood in leukemia. These cases have been col- 
lected by Frankel and Marischler, Froelich, Cabot, Kormoczi, and 
McCrae. Some of the reports refer to terminal septicemia which has 
resulted usually in a marked and rapid decrease of leucocytes, usually 
with an increase in the proportion of polynuclear cells. Frankel, 
who saw the leucocytes fall from 220,000 to 1200, refers this result 
to pure leucocytolysis. Such cases have been observed after typhoid 
fever, pneumonia, empyema, erysipelas, septicemia, tuberculosis, car- 
cinoma, and influenza (Kovacz). Beitzke, from observations in six- 
teen cases, concludes that all diseases which cause polynuclear leuco- 
cytosis tend to increase the proportion of these cells in leukemia. 
Distinct changes in leukemic blood do not invariably result from 
such intercurrent diseases. In cases where the infection is localized 
(empyema, erysipelas) the normal activities of the marrow seem to 
be stimulated, and while the leucocytes diminish the proportion of 
polynuclear cells increases (Freudenstein, Kovacz, Mliller'). Kraus 
has recently reported a reduction of from 393,000 to 4000 leucocytes 
in a few days as the result of double pneumonia and empyema. The 
viscera (marrow, liver, spleen) showed no evidence of leukemic infil- 
tration, and Kraus suggests that the suppurative process had not 
only transformed the blood, but had resolved the essential visceral 
lesions as well. Usually intercurrent infections diminish the volume 
of spleen and lymph nodes even w^ien, as in Miiller's case, the leuco- 
cytes are increased. After the subsidence of the infection the blood 
soon resumes its original condition (Grawitz), or even before the 
infection subsides the first effect may pass off, as occurred in Eisen- 
lohr's case, within fourteen days. 

Although no permanent improvement resulted in any cases suffering from 
intercurrent infection?, several attempts have been made to favorably influ- 
ence the course of leukemia by artificial leucocytosis. Jacob reduced the 
leucocytes from 850,000 to 282,000 in a few days by repeated injections of 
glycerin extract of spleen, but could not report any improvement in the 
patient. The same result was obtained by Richter using spermi?i. Richter 
and Spiro claim to have increased the leucocytes in leukemia from 170,000 to 
560,000 within three hours after injection of cinnamic acid, followed by prompt 
return to the previous condition. Heuck^ has also reduced the leucocytosis of 
leukemia by injection of tuberculin. In mild inflammatory processes there 
may be no effect upon the leucocytes of leukemia, as indicated by the cases 
of Richter and Heuck.^ 

Antemortem leucocytosis of considerable degree (172,000) was 
observed by Thorsch in a case complicated by pneumonia. In a 
case of lymphatic leukemia dying of septicemia, Miiller found, four 
days before death, 400,000 leucocytes when there had previously 
been but 180,000. A differential count was not made, but Miiller 
regarded the increase as referable to a polynuclear leucocytosis. 

Chronic infections have much less effect in altering the character 
of leukemic blood. Quincke and Stintzing reported a general 
improvement of the leukemic process during acute miliary tuber- 
culosis and during an exacerbation of chronic phthisis. 



LEUKEMIA. 247 

111 a case of lymphatic leukemia dying with carcinoma of the 
kidney Marischler found a decrease of leucocytes from 96,000 to 
48,000, with marked increase in the proportion of polynuclear cells. 

2. Spontaneous Changes in the Blood of Leukemia. A few instances 
are recorded in which the disease, as indicated by the blood changes, 
appeared to become transformed from one type into another. The 
first of these cases was that of Fleischer and Penzoldt, who observed 
splenic leukemia pass into lymphatic. It seems possible that this 
case may be placed with others described by FrankeP and Gerhardt, 
in which lymphatic leukemia began acutely with large lymphocytes, 
but progressed more slowly with small lymphocytes. Wey observed a 
case of myelocythemia in wdiich, within ten weeks, the polynuclear cells 
fell from 33.5 per cent, to 3.7 per cent., the mononuclears rose from 
66.5 to 96.3 per cent., among which Avere neutrophile myelocytes, 
large hyaline cells, and a few lymphocytes. This and Reiman\s case 
represent a series of transformations sometimes observed, in which 
the disease begins with a considerable proportion of polynuclear 
neutrophile cells, passes through a stage in which myelocytes exist in 
high proportions, and ends in more or less fulminant form, with many 
large cells deficient or entirely lacking in neutrophile granules. 

Gerhardt observed the blood of a case of leukemia of marked grade 
pass into that of pernicious anemia, the excess of leucocytes disap- 
pearing in three days. The possible transformation of pernicious 
anemia into leukemia has already been discussed. 

Pseudoleukemia has been described as changing into leukemia in 
several cases. (See Pseudoleukemia.) 

In view of the occasional reports of cases of leukemia in which 
the diagnosis rested upon the study of cadaveric blood, reference 
may be given, but with some caution, to the report by Seelig, of a 
case in which during life many myelocytes but few lymphocytes 
were found, while in the blood of the cadaver only lymphocytes were 
encountered. ^ ^; 

Chemistry. Specific Gravity. The specific gravity of the blood 
is usually reduced, owing principally to the loss of Hb. But leu- 
kemia is one condition in which Hb is often replaced by other 
albumins, so that the gravity of the blood is relatively high in com- 
parison to the Hb-content, and in exact proportion to the increase 
of leucocytes. Thus Diebella reports a case with 2,600,000 red 
cells, 750,000 leucocytes, and specific gravity of 1.060. The lowest 
observations are placed by Grawitz at 1.036. The low figures are 
usually seen in cases complicated by hemorrhages or other causes of 
secondary anemia. The specific gravity of the serum has been 
found by Grawitz and by Taylor to fall within normal limits, 1.023 
to 1.030. 

Alkalescence. The alkalescence of leukemic blood has been found 
by V. Jaksch, Peiper, and others to be much diminished. Early 
observers found the blood distinctly acid soon after death (Scherer), 
probably owing to the postmortem formation of acids, v. Noorden 
referred the diminished alkalinity to the development of acids during 
life. Lactic and formic acids have been isolated from the fresh 



248 SPECIAL PATHOLOGY OF THE BLOOD. 

blood by Scherer, Mosler, and others, and acetic acid, after death 
only, by Hosier. 

Albumins. Fibrin has been found in excessive quantity, 5.7 per 
cent, (normal 0.25 per cent.), by Parkes, but in chronic cases with 
severe anemia it is diminished (Robin). 

Peptone. Considerable interest attaches to the demonstration, first 
by Bockendahl and Landwehr, of considerable traces of peptone in 
the splenic pulp and in the blood of leukemia. This observation has 
lately been verified by Mathes, who, however, has shown that the 
principle in question is not Kuhne's peptone, but deutero-albumose. 
Freund believes that the retarded coagulation of leukemic blood is 
largely referable to the presence of albumose. The products of the 
excessive destruction of leucocytes have been traced in the presence 
of their various derivations in blood and urine. 

Nucleo-albumin and deutero-albumose, but not peptone, have been 
isolated from the serum by Mathes ; mucin or a closely allied sub- 
stance by Scherer and others ; and a principle resembling gluten by 
Salkowski. 

Xanthin bodies, which represent further decomposition products of 
leucocytes, have been found in the spleen and blood by Scherer, and 
many others The xanthin bodies of Kossel are more abundant and 
more easily recognized in leukemic than in normal blood. 

Uric acid has been found in traces by Mosler, Fowlwarczny, Klem- 
perer, and Weintraud. An excessive excretion of uric acid in the 
urine of leukemia has often been observed, and Magnus-Levy 
reported as high as eight grains daily, but since the most abundant 
appearance of leucocytes need not indicate the time of their greatest 
destruction, there is no parallel between the excretion of this prin- 
ciple and the excess of white cells in leukemia (Minkowski, Wey). 
Gumprecht^ finds that in those cases of leukemia in which uric acid 
excretion is normal there is an increase of ^' alloxurkorper,'' which 
consists of alloxan, urea, uric acid, and other principles of similar 
significance with uric acid. 

Glycogen. An increased quantity of glycogen has been extracted 
by Salomon and by Gabritschewsky. The fat-extract has been 
found distinctly increased by Robertson, Isambert (0.72 per cent.), 
and Freund and Obermayer. 

Tyrosin was isolated by Fowlwarczny, and lecithin and cholesterin 
from the blood of a hematoma by Freund and Obermayer. 

Of inorganic principles the iron has uniformly been found dimin- 
ished (2.24 to 2.97 per cent, of ash), usually in proportion to the loss 
of Hb (Strecker, Scherer, Freund, and pbermayer). 

Phosphorus, sulphur, and sodium were much increased and potas- 
sium and chlorine much diminished in Freund and Obermayer' s^ case, 
while the total salts were moderately increased. 

Charcot-Leyden Crystals. Robin first observed these peculiar 
crystals in the tissues of a leukemic cadaver, and they were described 
by Charcot and Robin in 1853. Zenker later (1855) claimed priority 
in their discovery. They were found in all parts of the circulation 
in a case examined after death by Wallace in 1855. Later they 



PLATE XL 




Mast Cells. (Ehrlieh's Dahlia-stain.) 



LEUKEMIA, 249 

were carefully studied by Charcot and Vulpian, who described 
theiu as colorless, refractive, elongated octahedra, 0.016 X 0.005 
mm., or occasionally of much larger dimensions, insoluble in cold 
water, alcohol, ether, or glycerin, soluble in hot water and in most 
acids and alkalies. After death they appear in the blood, exudates, 
and especially in the spleen, and their numbers increase with post- 
mortem changes in the tissues. Like most other crystals of post- 
mortem formation, they are often seen in or on the leucocytes. 
Their occurrence in sputum and relation to eosinophile cells was 
pointed out by Charcot and Leyden. According to Neumann,^ 
they are found in leukemia only when the blood contains many large 
cells with abundant cytoplasm and large nuclei, and hence are not 
seen in lymphatic leukemia. Chemically they were regarded by 
Charcot as albuminates, by Salkowski as mucinous. Lately Pohl has 
shown that they are identical with Bottcher's spermin crystals, which 
are a product of the destruction of the nucleins of disintegrating 
cells, and probably consist of spermin phosphate. Scherer also con- 
cluded that they are composed of phosphoric acid and an organic 
base. 

They were obtained in the blood drawn during life by Neumann 
and later by many others. 

They are not peculiar to leukemia, but appear in the sputum of 
asthma, in feces and mucus surrounding intestinal parasites, and 
have been found in the fetal blood in simple anemia (Gowers). 

Lewy states that eosinophile granules may be thrown down in the form of 
Charcot-Leyden crystals by fixation of tissue containing eosinophile leuco- 
cytes in magnesium sulphate, 1 part ; water, 7 parts ; or sodium sulphate, 1 
part; water, 10 parts. The tissues thus fixed should be thoroughly washed in 
water and hardened in alcohol. 

The Diagnosis of Leukemia. In no other department is the 
examination of the blood to be interpreted with greater certainty in 
one case or greater reserve in another than in its application to the 
various types of leukemia. 

1. The changes in the blood may yield positive diagnostic signs of 
leukemia. 

This result is obtained in the great majority of cases of both 
types, whether acute or chronic. 

These signs are briefly : 

In Myelocythemia. An excessive leucocytosis (1 50,000 to 1 ,000,000). 

A large number and considerable proportion of neutrophile mye- 
locytes (20 to 60 per cent.). 

A large number of eosinophile cells (3000 to 100,000) of which 
many are mononuclear and exhibit very large densely staining 
granules. 

An excessive number of polynuclear neutrophile cells. Charac- 
teristic changes in the red cells. 

To these may be added : The presence of many mast-cells, many 
nucleated red cells, mitotic nuclei in leucocytes, extreme and pecu- 
liar degenerative changes in leucocytes. 



250 SPECIAL PATHOLOGY OF THE BLOOD. 

In Chronic Lymphocythemia. An excessive leucocvtosis (150,000 
to 1,000,000). 

The presence of 85 to 99 per cent, of lymphocytes. 

Scanty numbers of myelocytes, eosinophiles, nucleated red cells, 
and mast-cells. 

For the positive diagnosis of either type of the disease the essen- 
tial point is the excessive leucocytosis, at least 150,000 cells, of 
which a considerable proportion are myelocytes or a still higher 
proportion are lymphocytes. 

Xo other condition thus far observed yields such characters in the 
blood in the presence of which the diagnosis of leukemia is estab- 
lished beyond doubt. 

2. The changes in the blood may justify only a probable diagnosis 
of leukemia. This situation is encountered under several condi- 
tions. 

(a) In myelocythemia the effect of intercurrent infections may so 
reduce the number of leucocytes, and especially the proportion of 
myelocytes, that the blood does not differ from that of some cases 
of acute inflammatory leucocytosis with 5 to 16 per cent, of myelo- 
cytes. 

(6) In the less marked stages of lymphocythemia, especially of the 
acute form, the number and proportion of lymphocytes may be far 
from characteristic of leukemia. When there are less than 150,000 
white cells and less than 90 per cent, of lymphocytes the condition 
of the blood does not differ from that seen in some forms of inflam- 
matory leucocytosis, or of lymphocytosis in the secondary anemia of 
children, or of the obscure condition called '^ v. Jaksch's anemia.'^ 
In inflammatory lymphocytosis, however, there are always a fair 
proportion of polynuclear leucocytes, which are very scanty in 
lymphemia, and the lymphocytosis is usually transient. 

In secondary anemia the lymphocytosis is seldom excessive, the 
proportion of lymphocytes is usually lower, and a few myelocytes, 
eosinophiles, and nucleated red cells are commonly present. 

In '^ v. Jaksch's anemia '' the lymphocytes are usually less numer- 
ous, there are more large hyaline mononuclear leucocytes than are 
usually seen in lymphemia of equal chronicity, and myelocytes, 
eosinophiles, and many nucleated red cells are usually present. 

Frankel has classed as acute lymphemia certain obscure cases attended with 
moderate hyperplasia of Jymph nodes and the presence in the blood of a 
considerable number of cells regarded by some as large lymphocytes. Frankel's 
cases have not been fully accepted by his countrymen, and Grawitz especially 
has shown that the above condition of the blood is not pathognomonic of 
lymphemia, while Benda has paved the way for the division of these cases 
into other categories, including acute myelocythemia. Frankel's cases may 
belong in the class of lymphocythemia, but the condition of the blood is not 
characteristic, and the result of his autopsies is inconclusive. 

3. In some stages of leukemia the blood may fail to furnish indi- 
cations of the nature of the disease, which may then be overlooked. 

(a) Intercurrent infections have been shown to temporarily trans- 
form the blood of leukemia into that of inflammatorv leucocvtosis. 



LEUKEMIA. 251 

(h) In a case of acute myelocythemiaj witli the disease fully estab- 
lislied, the \Yriter found on first examination, 5 per cent, of myelo- 
cytes with a leucocytosis of ordinary inflammatory grade. Later the 
myelocytes increased to the lower limits of leukemia, but a positive 
diao:nosis was not established until the marrow was examined micro- 
scopically. 

(c) Most writers agree that the early stages of leukemia often 
escape detection, and that many spurious cases have appeared in the 
literature. 

BiBLIOGEAPHY. 

Leukemia. 

Ambros. Inaug. Diss., Munchen, 1893. 

Arnold. Yirchow's Archiv, Bd. 97, p. 107. 

Askanazy. Virchow's Archiv, Bd. 137, p. 1. 

Audeod. Traite de mal. de Fenfance (Grancher), T. ii. p. 112. 

Bard. Lyon med., 1888, p. 239. 

Becquerel, Rodier. Recherches sur le Sang., 1845. 

Beitzke. Inaug. Diss., Kiel, 1899. 

Benda. XV. Cong. f. inn. Med., 1897, p. 371. 

Bennett. Edin. Med. Jour., 1845, vol. Ixiv., p. 413. Monthly Jour. Med. Sci., 
1851-52, XII., XIIL, XIV. 

Biesiadecki. "Wien. med. Jahrb., 1876, p. 233. 

Bignavn. Twentieth Cent. Pract., Article '' Malaria," 1900. 

Birch-Hirschfeld. XV. Cong. f. inn. Med. 

Bizzozero. Virchow's Archiv, Bd. 79, p. 378. 

Bockendahl, Landwehr. Virchow's Archiv, Bd. 84, p. 561 

Bollinger. Virchow's Archiv, Bd. 59, p. 341. 

Bonardi. Rev. gen, ital. di clin. med., 1889, No. 5. 

Bottger. ^ Virchow's Archiv, 1858, Bd. 14, p. 483. ^ Ibid., 1866, Bd. 36, p. 342. 

Bramwell. Cited by Pawlowsky. 

Cadiot, Roger. Path, du Sang. Traits de med. (Charcot), Paris, 1892. 

Cameron. Cited b)^ Stengel, Twentieth Cent. Practice, vol. ii. 

Casali. Rev. clin. Bologna, 1872, vol. ii, p. 118. 

Charcot, Robin. Compt. Rend. Soc. Biol., 1853, p. 44. 

Charcot, Vidpian. Gaz. Hebdom., 1860, p. 756. 

Cornil. Archiv d. phys. norm, et path., 1887, T. x. p. 46. 

Cornil, Ranvier. Histol. path. 

Craigie. Edin. Med. Jour., 1845, vol. Ixiv. p. 400. 

Denning. Munch, med. Woch., 1901, p. 140. 

Dock. Amer. Jour. Med. Sci., vol. cvi. p. 152. 

Donne. Cited by Gowers, Lancet, 1878, vol. i. p. 550. 

Eberth. Virchow's Archiv, 1868, Bd. 43, p. 8. 

Ebstein. Deut. Archiv khn. Med., Bd. 44, p. 343. 

Ehrlich. Gesam. Mittheil., 1891. 

Eichhorst. ^Virchow's Archiv, Bd. 130, p. 365. ^ibid., Bd. 113. 

Eisenlohr. Virchow's Archiv, 1878, Bd. 73, p. 56. 

Engel. Deut. med. Woch., 1897, pp. 118, 137. 

Erb.~ Virchow's Archiv, 1865, Bd. 34, p. 138. 

Ewing. N. Y. Med. Jour., 1895, vol. ii. p. 161. 

Fermi. Cited by Litten. 

Fleischer, Penzoldt. Deut. Archiv klin. Med., Bd. 26, p. 368. 

Fowlwarczny. Deut. Zeit. f. prak. Med., 1875. 

Frankel. ^Deut. med. Woch., 1895, p. 666. ^XV. Cong. f. inn. Med. 

Freudenstein. Inaug. Diss. Berlin, 1895. 

Freund, Obermayer. ^ Zeit, f. phvsiol. Chem,, Bd. 17, p. 318. - Ibid., Bd. 15, 
p. 310. 

Friedrich. Virchow's Archiv, Bd. 12, p. 37. 

Froelich. Wien. med. Woch., 1893, p, 285. 

Fuller. Lancet, 1846, vol. ii. p. 43. 

Gabritschewsky . Archiv f. exper. Path., Bd. 28, p. 272. 



252 SPECIAL PATHOLOGY OF THE BLOOD. 

Gerhardt- XV. Cong. f. inn. Med., p. 382. 

Gilbert. Path, du Sang. Traite de Med. (Charcot), Paris, 1892, vol. ii. p. 457. 

Gowers. Re^^lolds' Syst. Med., 1879, vol. v. p. 216. 

Grawitz. Klin. Path, des Blutes, 1902. 

Greene. N. Y. Med. Jour., vol. xlvii. p. 144. 

Greime. Berl. klin. Woch., 1892, No. 33. 

Gumprecht. ^Deut. Archiv klin. Med., Bd. 57, p. 523. ^Cent. f. Path., 1896, 
No. 20. 

Guttmann. Berl. klin. Woch., 1891, p. 1109. 

Hajek. Wien. klin. Woch., 1897, No. 20. 

Hayem. Du Sang., pp. 382, 856, 857. 

Herzfeld. N. Y. Polyclmic, 1894. 

Heuck. ^ Virchow's Archiv, Bd. 78, p. 475. ^ Deut. med. Woch., 1891, p. 747. 

Hinterherger. Deut. Archiv klin. Med., Bd. 48, p. 324. 

Hintze. Arch. klin. Med., Bd. 53, p. 377. 

Hirschlaff. Deut. Archiv khn. Med., Bd. 62, p. 314. 

Isambert. Cited by Mosler. 

Jacob. Cited by Grawitz, p. 127. 

Jaderholm. Cited bj^ Litten (Nothnagel, Spec. Path.), p. 148. 

V. Jaksch. Zeit. f. klin. Med., Bd. 23, p. 187, also Klin. Diagnostik. 

Jolly. Arch, de med. exper., 1902, p. 73. 

Kelsch, Vaillard. Annal. de I'lnstitut Pasteur, 1890. 

Klebs. iVh-chow's Archiv, 1867, Bd. 38, p 190. ^ Eulenberg's Realencyc, 
Bd. 1, p. 357. 

Klein. Cited by Pawlowsky. 

Klemperer, Weintraud. Deut. med. Woch., 1895, No. 40, V. B, 

Kormoczi. Deut. med. Woch., 1899, pp. 238, 775. 

Kottman. Inaug. Diss. Bern., 1871. 

Kottnitz Berl. klin. Woch., 1890, No. 35. 

Kovacz. Wien. klin. Woch., 1893, p. 701. 

Kraus. Prag. med. Woch., 1899, No. 41. 
■ Lannois, Regaud. Arch. d. med. exper., 1895. 

Lauenberg. Archiv f. Gyn., Bd. 40, p. 419. 

Leube, Fleischer. Virchow's Archiv, Bd. 83, p. 124. 

Lewy. Zeit. f. khn- Med., Bd. 40, p. 59. 

Limbeck. Prag. med. Woch., 1893, Nos. 12-14. 

Litten. ^ Berl. klin. Woch., 1877, p. 256, also Krankh. d. Milz. (Nothnagel, 
Spec. Path.), p. 133, etc. ^ xi. Cong. f. inn. Med., p. 159. 

Lowit. ^ Sitzungsber. kais Acad. Wien., 1885, also ibid., 1887, Bd. 95, III. Abt., 
p. 22. 2 Die Leukaemie als Protozoeninfec. Also, XVIII. Cong. inn. Med., pp. 
251, 322. 

Magnus, Levy. Cited by Litten. 

Mannaberg. XIV. Cong. f. inn. Med., p. 252. 

Marischler. Wien klin. Woch., 1896, p. 686. 

Masius, Francotte. Cited bv Ebstein. 

Mathes. Berl. klin. Woch., "1894, pp. 531, 556. 
^ Mayet. ^ Compt. Rend. Acad. Sci., 1888, p 762. ^ Soc. med. de Lj^on, 1888, T. 
xxviii. p. 47. 

McCrae. Brit. Med. Journ., 1900, vol. i. p. 760. 

McGillavry. Schmidt's Jahrb., Bd. 192, p. 19. 

Michaelis. Zeit. f. klin. Med., Bd. 46, p. 87. 

Milchner. Zeit. f. klin. Med., Bd. 37, p. 194. 

Minkowski. XVII. Cong. f. inn. Med., 1899 

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Archiv, Bd. 114, p. 461. 

Mosler, Westphal. Semaine med., 1889, p. 372. 

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f. Path., 1894, p. 628. 

Muller, Rieder. Deut. Archiv klm. Med., Bd. 48, p. 96. 

Mursick. Amer. Jour. Med. Sci., vol. Ixix. p. 449. 

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1878, p. 607. 

V. Noorden. Path, des Stoffwechsels, 1893, p. 342. 

Obrastzow. Deut. med. Woch., 1890, p. 1150. 



LEUKEMIA. 253 

Osterwald. Archiv f. Ophthal.. Bd. 27, p. 224. 

Palma Deut. med. Woch., 1892, p. 784. 

Pappenheim. Zeit. f. klin. Med., Bd. 39, p. 171. 

Parkes. Med. Times, 1851. 

Pawlowsky. Deut. med. Woch., 1892, p. 641. 

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Pohl. Deut. med. Woch., 1895, p. 475. 

Ponfick. Virchow's Archiv, Bd. 67, p. 368. 

Quincke. Miinch. med. Woch., 1890, p. 19. 

Reed. Amer. Jour. Med. Sci., 1902, vol. cxxiv. p. 653. 

Renaut Archiv de Phj^siol., 1881, T. xiii. p. 649. 

Richter. Cited bv Grawitz 

Richter, Spiro. Ai-chiv f. exper. Path., Bd. 34, p. 289. 

Rieder. "Leucocytose." 

Rindfleisch. Lehrbuch d. path. Gewebel. 

Robertson. Cited by Mosler. 

Roux. La Prov. Med., 1890, p. 280. 

Salomon. Charite-Annalen, 1878, vol. v. p. 139. 

Salkou'ski. Virchow's Archiv, Bd. 81, p. 166, also Bd. 50. 

Sanger. Cited by Stengel, Twentieth Cent. Practice, vol. ii. 

Schede, Stahl. Mitiheil. a. d. Chir. Abt., Friedrichshain Hosp. Berlin, Leipzig, 
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Scherer. Annal. de Chimie et de Pharm., T. cxliv. 

Schwarze. Ehrlich's Gesamt. Mittheil. 

Seelig. Arch. f. khn. Med., Bd. 54, p. 537. 

Senator. Berl. khn. Woch., 1882, p. 533. 

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Steinhrugge. Zeit. f. Ohrenheilk., 1886, p. 238. 

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Thorsch. Wien. klin. Woch., 1896, p. 395. 

Troje. Berl. klin. Woch., 1892, p. 285. 

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Utheman. Ehrlich's Gesamt. Mittheil. 

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Ziegler. Lehrbuch d. Allg. u. Spec. Path. Anat. 

Zenker. Deut. Archiv klin. Med., 1876, p. 125. 



CHAPTEE IX. 

PSEUDOLEUKEMIA. 

Definition. Pseudoleukemia is a primary disease of the lymph 
nodes and lymphatic structures, characterized by progressiye enlarge- 
ment of various chains of lymph nodes, and by secondary multiple 
growths of lymphoid tissue throughout the lymphatic system. It is 
of toxic and usually of infectious origin, and its essential feature is 
an extreme hyperplasia of lymphocytes, which approaches or reaches 
the grade of a neoplasm. 

Historical. The first attempt to demonstrate the specific character 
of the lymphadenopathy of the disease appeared in 1828, when 
Craigie called attention to the difference between certain firm tumors 
of lymph nodes and the caseating, scrofulous, and the cancerous 
enlargements. In 1832 Hodgkin described several cases observed 
chiefly at Guy's Hospital, some of which were cancerous, tubercu- 
lous, or syphilitic, but two of which were undoubtedly genuine 
examples of pseudoleukemia. He distinguished the " organized '^ 
nodes from the caseous and cancerous ones. 

Before the discovery of leukemia, therefore, it was known that 
there are enlargements of the lymph nodes apart from cancer and 
tuberculosis. In 1839 Yelpeau drew attention to the occurrence of 
hypertrophied lymph nodes apart from scrofula. In 1856 Wilkes 
described several cases, which he regarded as a special form of dis- 
ease of lymph nodes, but did not fully distinguish the lesions from 
those of tuberculosis. 

The first complete description of the malady appears to have been 
that of Wunderlich, 1858, who noted an idiopathic origin of the dis- 
ease, and the cellular character of the new-growths in both nodes and 
spleen, mentioned the severe anemia, and called attention to the 
absence of the extreme leucocytosis which characterizes leukemia. 
In the same year, 1858, Billroth described the histological structure 
of the enlarged nodes, noting the limitation within the capsule, the 
obliteration of follicles and of lymph sinuses and vessels, the pro- 
liferation of cells by nuclear division, and concluding that the 
hyperplasia is closely related to and may pass into sarcomatosis. 
Eecognizing in the condition a tumor of lymph nodes of fatal ten- 
dencies, but differing from sarcoma, he employed the term ^^ malig- 
nant lymphoma" as specially applicable to this condition. In 1864 
the general pathological features were described by Virchow, under 
the term "lymphosarcoma." Gohnheim in 1867 described a case, 
and, noting especially the absence of leucocytosis, suggested the term 
" pseudoleukemia." 

The nearly constant affection of the spleen was noted by the earlier 
observers, Wilks, Woillez, Griesinger, Miiller, and Strtimpell, and 



PSEUDOLEUKEMIA. 255 

the prominence of this symptom in some cases led Griesinger to 
employ the term " spleuic anemia ^^ for such forms of the malady. 

In France, Bonfils described a case in 1858, using the designa- 
tion ^' cachexie sans leukemia/^ on account of the absence of leuco- 
cytosis. 

A few other examples of the disease were reported before 1865, 
when Trousseau described in detail the clinical characters and pro- 
posed the term " adenia." French writers from Trousseau to Gilbert 
have regarded the condition as very closely related to or identical 
with leukemia, employing the term " lymphadenie aleukemiqueJ' 

In 1870 a full description of the disease, clinical and pathological, 
with historical notes to date, was published by Murchison and San- 
derson. Cornil and Eanvier, in 1867, very fully described the 
histological structure of the nodes, regarding the process as a true 
lymphadenoma. In 1887 Ebstein/ described an acute form of the 
malady. Later writers have described similar cases, possibly includ- 
ing among them some conditions not related to pseudoleukemia (Banti, 
Potain, Bruhl). 

The peculiar localization of the lesions to different structures has 
been illustrated in many reported cases. Bonfils and Trousseau 
claimed that the spleen need not participate at all in the lesion. A 
special affection of the tonsillar ring was described by Demange, and 
of the intestinal mucosa by Gilly, and later by many others. A 
testicular form has been described by Monod and Terillon. A case 
of Reineberg's indicates that the lesion may be limited to the marrow. 
Many have regarded the anemia infantum pseudoleukemiea of v. Jaksch 
as the splenic form of Hodgkin's disease occurring in an infant 
(Luzet, Gilbert). 

The dermal type of the disease has been described by many writers, 
including Biesiadecki, Kaposi, Hochsinger and Schiff, and Joseph, 
but appears to have been first described in France by Gillot. 

Anatomical Characters. Lymph Nodes. The essential lesion in 
the disease is an extreme hyperplasia of lymphocytes. In some 
cases, especially in the early or active febrile stages, there are promi- 
nent signs indicating that the hyperplasia is inflammatory, but in 
other cases the lesions are those of a simple hyperplasia approaching 
the neoplastic grade, and the inflammatory changes are in the back- 
ground. 

Gowers has described in different nodes of the same case various 
stages between simple inflammatory and neoplastic hyperplasia of 
lymphocytes. The essential lesion may, therefore, be inflammatonj 
hyperplasia or lymphadenoma. 

In the typical chronic cases one lyraph node in a chain is affected, followed 
by the other members of the chain, or the entire chain is aftected simultane- 
ously. The disease seldom spreads by gradual extensions from one chain to 
another, but suddenly iuvolves a new chain on the same or opposite sides of 
the body. Sarcoma of lymph nodes affects the intervening tissues between 
chains of nodes. For a long period the swollen nodes are retained in their 
capsules, but late in progressive cases the members of the chain are variously 
fused and their capsules largely obliterated. This fusion may result either 
from rupture of the capsules or from periadenitis. 



256 SPECIAL PATHOLOGY OF THE BLOOD. 

It is regarded by some as an important distinction of Hodgkin's disease 
that secondary growths arise only in pre-existing lymphoid structures, while 
in lymphosarcoma the secondary growths are indiscriminate and more dif- 
fuse. 

Microscopic examination shows the new tissue to be composed of 
lymphocytes supported by reticular tissue. There are considerable 
variations in the character, both of the cells and of the reticular 
tissue. The cells are usually lymphocytes of small and medium size, 
among which are a few polynuclear leucocytes, exfoliated endothelial 
cells, and a few small giant cells. Eosinophile cells are frequently 
but not always found in considerable abundance (Goldman, Kanter). 
This local eosinophilia is regarded by Dietrich and Fischer as of 
diagnostic importance. Reed found it in six of eight cases. Its 
presence is regarded by most pathologists as an argument favoring 
the belief in a tuberculous origin of such growths, as eosinophile cells 
are so frequently found in atypical tuberculous lesions. The lympho- 
cytes are either diffusely distributed or the normal follicles may be 
preserved for a long period. In the early stages or in less active 
growths the lymph paths are preserved, but later are obliterated. 
The reticular tissue is frequently less abundant than in the normal 
node ; later a diffuse fibrosis occurs and the proportion of cells 
diminishes. The varying proportions of cells and connective tissue 
yield soft and cellular or hard and fibrous growths. The latter is 
probably a later stage of the former condition, but all stages are com- 
monly seen in different nodes of the same subject, and dense nodes 
are said to have been replaced by softer ones (Gowers). There is 
little tendency in these structures toward caseation, or suppuration, 
or hyaline changes of chronic tuberculosis. 

The lymph nodes of pseudoleukemia may not differ in microscopic 
structure from those of lymphatic leukemia in any known particular. 
Nevertheless, they commonly show more of the signs of chronic 
inflammation and less of the distinctly neoplastic features. In mye- 
locytic leukemia the lymph nodes commonly show a diffuse growth 
of larger mononuclear cells. According to Birch-Hirschfeld^ the 
nodes of leukemia can be injected through afferent vessels and the 
fluid w^ill pass through into the efferent vessels, while in pseudo- 
leukemia the injection is imperfect and fluid fails to pass through. 
Attempts to demonstrate lymph vessels about pseudoleukemic nodes 
have often failed (Billroth), but sometimes they are found distended 
with lymph. The occlusion of lymph paths may prevent the afflux 
into the general circulation of cells from lymph nodes, but it still 
remains an obscure fact that the very abundant and unusually diffuse 
lymphoid deposits in the viscera fail to cause lymphocytosis. 

Relation to Lymphosarcoma. In many cases reported as pseudo- 
leukemia, especially of more acute type, the lymph nodes in the 
group are fused together, capsules and surrounding structures are 
infiltrated and destroyed, different chains are united by a continuous 
growth, and the process has all the gross characters of a malignant 
tumor. Such nodes show no traces of sinuses or follicles, but are com- 
posed of a diffuse growth of cells usually larger than lymphocytes. 



PSEUDOLEUKEMIA. 257 

often contaming giant cells and sometimes masses of fusiform cells. 
In some cases with more or less involvement of pre-existing lymph 
nodes multiple secondary growths of very wide distribution occur 
in situations where distinct collections of lymphoid cells do not 
normally exist. Thus the serous membranes, pleura, and peritoneum 
may be found studded with myriads of fine nodules of lymphoid 
tissue. In such cases the local original growth may or may not 
exhibit distinct sarcomatous characters. 

There appear to be all transitional forms between the chronic lymplio- 
mata and the rapidly growing, infiltrating, giant-celled lymphosarco- 
mata. In at least one case it has been possible to observe the 
transformation of pseudoleukemia into sarcoma of lymph nodes (Eisen- 
menger). Moreover, of the cases of pseudoleukemia which have 
passed into leukemia, some have shown the histological structure of 
giant-celled lymphosarcoma. There remains as a separate class of 
sarcoma of lymph nodes the spindle-celled sarcomata or endothelio- 
mata, which arise from the reticular stroma. 

Two views are possible regarding the classification of such growths. 
One may enlarge the scope of the term pseudoleukemia to include 
lymphosarcoma, or may throw out such cases of lymphosarcoma, and 
limit the application of the term to the lymphadenomata. 

In the present state of our knowledge it seems unwise to rob the 
terms Hodgkin's disease and pseudoleukemia of their specific meaning 
by including with the cases which resemble lymphatic leukemia those 
which possess all the characters of malignant tumors. It is admis- 
sible and convenient to limit the term pseudoleukemia, as is com- 
monly done, to cases exhibiting the following characteristics : general 
similarity to lymphemia without leucocytosis, considerable involve- 
ment of various chains of lymph nodes, in which the separate nodes 
long retain their identity, absence of involvement of intervening 
tissue between affected chains, development of secondary growths 
principally in pre-existing lymphoid structures, histological structure 
indicating slight malignancy of an inflammatory origin. 

Spleen. The spleen is always enlarged, usually to a very consid- 
erable size. Microscopically the lesion is found to consist in hyper- 
plasia of the lymphocytes in the Malpighian bodies with more or less 
obliteration of their outlines, in some increase in the cells of the 
pulp cords, and in hyperplasia and exfoliation of the endothelial cells 
resulting from chronic congestion and inflammation. While in some 
instances the enlargement of the Malpighian bodies produces mul- 
tiple tumor-like growths, more often these bodies are but slightly 
enlarged, and are not prominent. The early cellular stages of the 
splenic lesion may later be replaced by a diffuse deposit of fine 
fibrils of connective tissue running out froui the Malpighian bodies, 
and involving the pulp cords. 

Marrow. The hyperplasia of the lymphocytes in the marrow is 
usually not marked. The changes usually consist in moderate excess 
of lymphocytes, swelling, hyperplasia, and exfoliation of endothelial 
cells, and corresponding loss of the normal cells of the marrow. In 
some cases there are added the changes of secondary pernicious anemin. 

17 



258 SPECIAL PATHOLOGY OF THE BLOOD. 

Acute Pseudoleukemia. Various acute and fatal processes of 
somewhat uncertain nature have been classed with pseudoleukemia. 

1. That pseudoleukemia may run an acute course appears from 
the reports of Cohnheim, Eberth, and Falkenthal, in which the dis- 
ease lasted from eleven days to four and one-half months, and in 
which microscopic examination showed the presence of lymphadeno- 
matous hyperplasia of the nodes and metastatic growths in the 
viscera. These cases occurred in children under fifteen years. 

2. Chronic pseudoleukemia may suddenly assume a grave char- 
acter and prove rapidly fatal from the ulceration of enlarged lymph 
follicles in the intestines, as first shown by Berthen son's cases, and 
now not infrequently verified at the autopsy table. Usually such 
fulminant features in the disease are seen in the early stages of cases, 
which later subside and pursue a chronic course ; or in latent 
processes which have long existed without attracting attention ; while 
in other cases the acute course is referable to secondary infections 
grafted on the original process. 

. 3. Acute lymphosarcoma may run a rapidly fatal course and lead 
to changes in the viscera, which are very similar to those of pseudo- 
leukemia. Fagge collected several cases to illustrate this fact, but 
their real nature is not always apparent, and the microscopic reports 
were meagre. They were all attended with purpuric symptoms. 
As already stated, these cases cannot properly be included in the 
class of pseudoleukemia. 

The most rapid case of lymphosarcoma that the writer has seen lasted four 
months. The nodes showed a diffuse growth of mononuclear cells much larger 
than lymphocytes and a few giant cells. There was prompt recurrence of the 
tumor in loco, rapid metastases, marked anemia, and no leucocytosis. Much 
more rapidly fatal cases have been observed, while Birch-Hirschfeld's case of 
Hodgkin's disease following typhoid fever was fatal in six weeks. 

Relation of Pseudoleukemia to Leukemia. The similarity of 
the process in the lymphoid tissues in pseudoleukemia and leukemia, 
is strongly indicated by the histological features already described. 
The process in pseudoleukemia differs from that in lymphemia in its 
constant origin in the lymph nodes, whereas lymphemia originates 
in or constantly involves the marrow. In pseudoleukemia the lymph 
paths are occluded and the growth is more circumscribed, although 
usually producing larger tumors, while the signs of an inflammatory 
process are often distinct in one, while commonly lacking in the other. 

Pseudoleukemia may lead to the same changes in the marrow as 
are seen in lymphatic leukemia (Perrin, Schulz, Dyrenfuth, Kelch, 
Ponfick,^ Schmuziger, Baumgarten). 

The transformation of pseudoleukemia into leukemia has been re- 
ported in several cases Most of these on examination prove to be 
of uncertain nature, or were undoubtedly instances of terminal or 
moderate temporary leucocytosis in the course of some disease of 
the lymph nodes. 

Hosier reports an acute case in a child, aged fourteen years, whose blood a 
few weeks after the onset of the disease showed no leucocytosis, while about 
three weeks before death the white cells were as numerous as the red. The 



PSEUDOLEUKEMIA. 259 

varieties of cells were not stated. Senator has reported a case of transforma- 
tion of V. Jalisch's anemia into leukemia. The case of Fleischer and Pen- 
zoldt is th,e most significant. Their patient was a male, aged forty years, who 
suffered from enlargement of many lymph nodes for sixteen months before 
death. Four months after the beginning of the illness there was no leucocy- 
tosis, but after twelve months there was one lymphocyte to nine red cells. 
The spleen was moderately enlarged, the lymph nodes extremely large ; there 
was diffuse lymphoid infiltration of the liver, but the marrow of the femur 
was normal. The microscopic structure of the nodes was not reported, 
while the absence of a characteristic lesion in the marrow speaks against leu- 
kemia. Wende reports a case of pseudoleukemia beginning with multiple 
tumors of skin and lymph nodes with terminal lymphocytosis of 45,000 cells, 
96 per cent of lymphocytes appearing after the fourth month of the disease and 
one month before death. The day before death the leucocytes fell to 600. 
The marrow was unchanged. 

It thus appears that the statement that pseudoleukemia may pass 
into leukemia rests upon rather uncertain observations. The more 
recent case of Posselt is an apparently genuine example of the same 
transformation, but the clinical history is meagre. The remarkable 
case of Lucke's of lymphosarcoma with rupture into a vein and 
development of lymphatic leukemia is also of interest in this con- 
nection. One must, therefore, accept with considerable reserve the 
opinion that some forms of pseudoleukemia represent an aleukemic 
preliminary stage of leukemia. The vast majority of cases of pseudo- 
leukemia pursue a chronic course showing no tendency to develop 
leukemia, and recent experience does not support Rothe's belief, that 
^arly pleurisy and pneumonia carry off many cases of pseudoleuk- 
emia before the leukemic stage has had time to appear. Eisen- 
menger reports a case of pseudoleukemia which, after pursuing the 
ordinary course for four years, developed malignant characters infil- 
trating surrounding tissues and perforating the larynx. The pres- 
ence of 90,000 leucocytes in this case would have led many observers 
to suggest the presence of lymphatic leukemia as well. 

Relation of Pseudoleukemia to Pernicious Anemia. Runeberg 
reported a case showing pernicious anemia, which he regarded as 
an example of purely myelogenous variety of pseudoleukemia, on 
account of the lymphoid changes in the marrow. The transforma- 
tion, of pernicious anemia into pseudoleukemia was claimed to have 
occurred in a case described by Laache, and there can be no doubt 
that the marrow in some cases of pernicious anemia greatly resembles 
that of pseudoleukemia, as first noted by Scheby-Buch and Pepper. 
On evidence of this sort, Sevestre suggested that all cases of perni- 
cious anaemia fall in the class of pseudoleukemia, but this view cannot 
be supported on either clinical or anatomical grounds. 

Relation of Pseudoleukemia to Tuberculosis. That cases of 
tuberculous lymphadenitis cannot always be distinguished clinically 
from pseudoleukemia was early recognized, and so commonly ob- 
served that the scope of the disease was by some widened to include 
such cases. Many of the cases of so-called chronic intermittent fever 
with swelling of lymph nodes described by Pel, Ebstein/ Ronvers, 
and many others, probably belong in this class, as shown by Combe- 
male and Musser. 



260 SPECIAL PATHOLOGY OF THE BLOOD. 

The exact significance of these cases appears not to have been sus- 
pected until Askanazy, in 1888^ demonstrated tubercle bacilli in the 
swollen nodes of such a case. In most of the cases in which micro- 
scopic examination of the nodes was reported^ there were distinct 
evidences of tuberculous inflammation, in the presence of miliary 
tubercles, or caseous foci, or at least abundant hyaline degeneration, 
and often there was a general tuberculosis (Delafield), but Waetzoldt^s 
case furnished some nodes, showing pure lymphoid hyperplasia, with 
only very scanty and minute foci of hyaline material, although con- 
taining many tubercle bacilli in sections. Finally, Brentano and 
Tangl have described a chronic case in which, with tuberculous 
lesions in other regions, the lymph nodes showed no recognizable 
evidences of tuberculosis, not even minute hyaline areas, nor bacilli 
in section. Inoculation experiments, however, demonstrated the tuber- 
culous nature of the process. Numerous observers have recently 
reported similar cases, while Sternberg demonstrated the tuberculous 
nature of fifteen of eighteen routine cases. 

On this evidence, of which further confirmation appears desirable^ 
it is necessary to admit either that tuberculosis of lymph nodes may 
follow the most typical course of acute or chronic pseudoleukemia 
or that tuberculosis and pseudoleukemia may coexist. It is evident,, 
also that microscopic examination of lymph nodes is not a sufficient 
test of the tuberculous nature of lymphomata, and that the entire 
subject requires readjustment on the lines indicated above. 

That all cases of pseudoleukemia are not tuberculous, however, is 
indicated by the negative results of inoculation obtained by West- 
phal, Sciola and Carta, Fischer, Reed, and others, but it must be 
remembered that the inoculation of moderate quantities of tubercu- 
lous material in guinea-pigs is not always followed by tuberculosis. 

Miscellaneous Infectious Origin of Pseudoleukemia. Acute or 
chronic, non-tuberculous, inflammatory hyperplasia of lymph nodes- 
may reach sucli extreme degree as to resemble the condition found 
in pseudoleukemia. The reported cases of this character are numer- 
ous, and have arisen from a great variety of infections, as from 
carious teeth (Ebstein,^ Stengel), quinsy (Ponfick^), ulcerative pharyn- 
gitis (Chvostek), typhoid fever (Birch-Hirschfeld^). Other cases 
have been referred to otitis media, chancroid, eczema, etc. The 
writer has seen more extensive lymphoid hyperplasia in the intestine 
in typhoid fever than existed in two cases of pseudoleukemia dying 
with intestinal ulcerations. 

Microscopic examination, where reported, has shown that the 
hyperplasia of nodes is inflammatory in character and not lympho- 
matous, as in the cases of Lannois and Courmont, while metastatic 
growths are wanting. Many of these cases have resembled purpura 
hemorrhagica, as pointed out by Kossler and regarded by him a& 
evidence of infectious character. Lannois, Courmont, and Guiller- 
met isolated pyogenic cocci in their cases. 

The occurrence of these febrile forms of the disease and its fre- 
quent development after many forms of suppurative inflammation, 
especially of the mucous membranes, early suggested the idea that 



PSjE UB OLE UKEMIA. 261 

pseudoleukemia Is, in all instances, of infectious origin. This view 
was reached by Westphal, after a full review of the subject in 1893, 
and has since been maintained bv Barbier, Verdelli, and others. Ver- 
delli collected fifteen cases of pseudoleukemia, in which the presence of 
pyogenic organisms was demonstrated in the blood or lymph nodes, 
viz., staphylocoGGUs pyogenes aureus, seven times ; streptococcus 
pyogenes, three times ; pneumococcus of Fraenkel, once ; unidentified 
cocci or bacilli, four times. 

Barbier refers the failure of suppuration in these cases and the negative 
results of some inoculations to a diminished virulence of the germ or to rela- 
tive insusceptibility of the individual. The accumulating evidence points to 
the possibility of separating from true pseudoleukemia a considerable group 
of inflammatory hyperplasias of bacterial origin. At the same time it must 
be admitted that the micro-organisms in some of the above cases were prob- 
ably the cause of secondary infections only, and there are opposed to these 
positive results of culture a number of negative reports. 

That tertiary syphilis of the lymph nodes may occasionally pursue 
a clinical course indistinguishable from that of chronic pseudoleu- 
kemia has long been accepted by surgeons, and the existence of a 
syphilitic element in some cases which yielded to mercury has been 
pointed out by Lannois and Lemoine and others, Lowenbach's 
study of these cases indicates that the lesion closely resembles that 
of the tuberculous variety, with rather greater tendency to fibrosis. 
With few exceptions the syphilitic lymphomata have been of moderate 
size. 

It may be added that Lowit claims to have found the hemameba 
leukeniice magna in a case of pseudoleukemia. 

Summary of Etiology and Pathogenesis. It thus appears that 
the term pseudoleukemia applies to a group of cases showing 
chronic enlargement of the lymph nodes usually originated by or 
associated with an infectious agent, but in which the histological 
examination reveals a multiplication of cells, apparently beyond the 
limits of inflammatory hyperplasia, in some cases developing into 
lymphosarcoma, and possibly in rare instances into lymphemia. 
That the clinical course of the disease may be perfectly simulated by 
tuberculosis, and that the more or less specific histological changes 
in the nodes are in the majority of cases induced by the tubercle 
bacillus, there is no longer good reason to doubt. 

Such overgrowth of lymphocytes in pronounced degree is exhibited 
in some other manifestations of tuberculosis, so that no new char- 
acter of this micro-organism is required to account for its connection 
with Hodgkin's disease. 

It seems almost equally certain that other micro-organisms, the 
common pyogenic bacteria, and syphilis may give rise to the same 
lesions and history. The essential feature appears to be not a par- 
ticular micro-organism, but a particular clinical course and histolog- 
ical lesion. This lesion is an extreme hyperplasia of lymphocytes, 
which lies in the well-recognized border-land between inflammatory 
and neoplastic processes. In most cases the inflammatory features 
are distinct, and a tendency to fibrosis is evident. In others the 



262 SPECIAL PATHOLOGY OF THE BLOOD. 

grade of hyperplasia progresses until it seems to fall within the group 
of neoplasms. That the lymphatic hyperplasia of typical chronic 
Hodgkin's disease ever does fall distinctly into the group of true 
neoplasms may still be doubted. 

It is possible that the advent of a true neoplastic process affecting 
lymphocytes is revealed at once by the clinical features of lympho- 
sarcoma or lymphemia, in which case Hodgkin's disease is resolved 
into lymphosarcoma, on the one hand, and inflammatory hyperplasia, 
usually tuberculous, on the other. An essential feature, as pointed 
out by Grawitz, is the general systemic involvement giving rise to 
multiple lesions throughout the lymphatic system. It also appears 
that the peculiar clinical condition is not, as claimed by Grawitz, 
without a peculiar pathological basis, but is, on the other hand, char- 
acterized by a most striking cellular reaction, which has numerous 
counterparts within the domain of cellular pathology. It may even 
be claimed that the histological process is more distinctly limitable 
than is the clinical picture, especially in the cases of lymphosarcoma, 
which may resemble pseudoleukemia at a time when the histology of 
the nodes clearly indicates a malignant process. 

It remains to consider the significance of those cases in which dis- 
tinct tuberculous lesions are added to the lymphatic hyperplasia. 
Of these it may be said that the essential feature of pseudoleukemia 
is present, viz., the excessive hyperplasia of lymphocytes, and that 
the mere additional presence of the ordinary lesions of tuberculosis 
is insufficient ground for eliminating these cases from the category 
of pseudoleukemia, so long as they exhibit the usual clinical and 
anatomical features of the disease, ^or is it necessary to suppose 
that tuberculosis is here grafted upon some other process. Usually 
in such cases, the ordinary tuberculous lesions, if present at all, are 
coextensive with the simple hyperplastic changes, which is very 
unlikely to follow a secondary infection by tuberculosis. 

The existence of numerous transitional forms between frank tuber- 
culosis of lymph nodes and pseudoleukemia, between pseudoleukemia 
and lymphosarcoma, and between pseudoleukemia and lymphemia, 
as well as the increasing number of observations of the coexistence 
of tuberculosis and lymphemia, suggest that all of these conditions 
may at times have a common origin. 

The Changes in the Blood. 

Red Cells. It is a uniform observation that in the early stages 
of pseudoleukemia the anemia may be very slight. The red cells 
frequently number 5,000,000 or more when the nodes are distinctly 
swollen. With the progress of the lesion there is usually a progres- 
sive loss of red cells, which, however, is less marked than in corre- 
sponding stages of leukemia. In fatal cases there may be surprisingly 
little anemia, usually the cells fall below 3,000,000, and occasionally 
the condition of the blood resembles secondary pernicious anemia. 
In acute cases the anemia may rapidly increase, and the disease 
resembles a septic infection or a malignant new-growth. 



PSEUDOLEUKEMIA. 263 

In morphology the red cells usually show the changes of simple 
secondary anemia of chronic course. Laache has called attention to 
the very uniform size of the red cells in the average case. In some 
of the writer^s cases the cells have been very uniformly undersized. 
Later megalocytes deficient in Hb may appear, but they are seldom 
numerous, and do not lead to confusion with pernicious anemia. 
Laache also reports an obscure case regarded as showing the trans- 
formation of pernicious anemia into pseudoleukemia. 

Nucleated red cells are usually very scarce, even in late stages, and 
when present are usually of moderate dimensions. Jawein reports 
an obscure case of splenic type and afebrile course, in which there 
were 3840 to 5914 normoblasts. The condition of the blood 
resembled that of v. Jaksch's anemia, but the patient was an adult. 

The Hb is in all cases diminished. A low Hb-index is commonly 
seen in early stages or with slight diminution of red cells, while in 
advanced cases with marked reduction of red cells the Hb-index is 
usually higher. These characteristics are common to most secondary 
anemias. 

The anemia of the typical case of Hodgkin's disease stands in an 
intermediate position between simple secondary and pernicious 
anemia. It is usually much less marked than in corresponding 
stages of leukemia, and almost never approaches the type of perni- 
cious anemia. On the other hand, it is usually more marked than 
the general condition of the patient would lead one to suspect, thus 
differing from most forms of secondary anemia. As Grawitz has 
pointed out, the character of the blood changes offers little encour- 
agement of the tendency to find in this disease a condition related 
to either pernicious anemia or leukemia. 

Leucocytes. The number of leucocytes in the blood is consider- 
ably influenced by the character of the process in the lymph nodes. 
In the majority of cases the leucocytes are normal or diminished in 
number, and there is a tendency toward relative lymphocytosis. In 
many cases, however, the leucocytes are continuously increased, with 
periods of well-marked leucocytosis. The increase of Avhite cells 
may be considerable, but does not pass beyond the limits of inflam- 
matory leucocytosis, 50,000 to 60,000. Exceptions to this rule must 
be allowed in the cases of pseudoleukemia which appear to have 
passed into leukemia, while in Eisenmenger's case, which terminated 
with sarcoma, there were 90,000 leucocytes. A few eosinophiles are 
commonly seen in afebrile cases, while an occasional myelocyte has 
sometimes been encountered. 

The cases showing few white cells the writer has found to be 
usually the chronic ones of slow progress and without fever, while a 
high proportion of polynuclear cells, with or without absolute in- 
crease, usually belongs to the more rapid or the febrile cases. Lim- 
beck finds that when the polynuclear cells are increased the nodes 
usually show inflammatory changes, but when lymphocytosis is found 
the nodes approach more to the sarcomatous type. In lymphosar- 
coma, also, not simulating pseudoleukemia, the small lymphocytes 
may be very numerous. The writer has been unable to find any 



264 SPECIAL PATHOLOGY OF THE BLOOD. 

features in the blood distinguishing between pseudoleukemia and 
frank chronic tuberculosis of lymph nodes. 

Diagnosis of Pseudoleukemia. 1. From myelocytic or pro- 
nounced lymphatic leukemia the diagnosis is readily accomplished 
by the examination of the blood, demonstrating the absence of char- 
acteristic leucocytosis. 

2. From less pronounced cases of lymphatic leukemia the diag- 
nosis may not in every instance be possible. Usually the excess of 
leucocytes in pseudoleukemia affects the polynuclear type, but as the 
histological structure of the nodes approaches sarcoma the lympho- 
cytes may be greatly increased. 

3. In tuberculosis of lymph nodes the diagnosis may require 
microscopic examination of the nodes. If tuberculous, these may 
show (a) distinct tuberculous lesions, miliary tubercles, and cheesy 
areas ; {h) small areas of hyaline material associated with demon- 
strable tubercle bacilli ; (c) lymphoid hyperplasia, without any trace 
of distinct inflammatory changes and without bacilli in dcQionstrable 
numbers. Such nodes should be tested by inoculation. 

4. Non-tuberculous inflammatory hyperplasia of lymph nodes 
usually causes irregular fever, polynuclear leucocytosis, and suppura- 
tion of the nodes. It is probable that some pyogenic infections of 
lymph nodes may run the course of subacute pseudoleukemia. 

Chronic Splenic Anemia. This term is commonly applied to a 
group of cases characterized by idiopathic enlargement of the spleen 
and anemia, but without enlargement of the lymph nodes. While 
the clinical aspects of these cases are rather characteristic, the under- 
lying pathological conditions have been found so diverse or obscure 
that many deny that any peculiar condition exists to which such a 
term can be properly applied. This state of affairs is largely owing 
to the incomplete investigation of the clinical history and the patho- 
logical lesion in the spleen. The writer believes that after all recog- 
nizable and well-understood conditions have been separated from this 
group there remains a set of cases of somewhat peculiar clinical 
characteristics and with somewhat specific lesion in the sjileen to 
which the name chronic splenic anemia may be given. 

To reach this conclusion one must separate from the group of cases 
of large spleen with anemia the following conditions, all of which 
are clearly distinct from the others. 

Syphilis of the spleen. Gummata. 

Large round-celled sarcoma of the spleen. 

Chronic splenitis of the type of Graucher {epitheliome ■primitive). 

Chronic malarial splenitis. 

Splenomegaly of anemia infantum (v. Jaksch). 

Splenomegaly secondary to cirrhosis of the liver. 

Many writers include under splenic anemia the anemia infantum 
of v. Jaksch — a practice which is entirely unwarranted seeing that 
the histology of the viscera, both liver and spleen, and of the blood 
is quite different in these conditions. 

Others include under splenic anemia the peculiar condition of the 
spleen described by Gaucher as epitheliome prnmitive, although the 



PSEUDOLEUKEMIA. 265 

splenic lesion indicates positis^ely that this condition must stand by 
itself. 

There remain for consideration the splenomegaly of Banti's disease, 
that of marasmic infants suffering from chronic catarrhal gastro- 
enteritis, and that of certain cases in which the lesion of the spleen 
is that of chronic hyperplastic splenitis, but with which there is 
neither gastroenteritis nor cirrhosis. 

The writer has studied the histological lesion in the spleen in each 
of these three conditions without finding any essential differences. 
All show phases of chronic hyperplastic splenitis, with variations 
only in proportion of cells and diffuse connective tissue 

AYhile the splenic lesions in these cases do not differ essentially 
from some stages of the lesion of pseudoleukemia, yet it appears 
unwise to regard any of these cases as examples of splenic pseudo- 
leukemia, because none of them develop the lesions in the lymph 
nodes of that disease while the spleen is often larger than that of 
pseudoleukemia. 

The question remains, therefore, to determine the relation between 
the chronic splenic anemia of adults, young or old, that of Banti's 
disease, and that of marasmic infants suffering from chronic gastro- 
enteritis. 

That all of these conditions are referable to intestinal toxemia has 
been repeatedly claimed ; and it may be that all represent different 
stages of essentially the same process. The majority of continental 
writers accept this view. 

Until this etiological relation is established and until it is proven 
that a marasmic infant with splenomegaly may pass through adoles- 
cence as a case of chronic splenic anemia and die later with the lesion 
of Banti's disease, it may be just as well to apply the term of splenic 
anemia to the supposed intermediate stage of the process. 

The typical case of splenic anemia does not suffer from gastro- 
enteritis and seldom gives such a history, while the disease com- 
monly persists for years without developing the cirrhosis of Banti. 

A description of the changes in the blood of this particular group 
of cases is rendered difficult because current reports usually refer to 
cases of uncertain nature, and include, especially, examples of v. 
Jaksch's anemia and Banti's disease. In the more limited group 
described above, the changes in the blood are those of a slowly pro- 
gressive secondary anemia without leucocytosis and with relative 
lymphocytosis. 

The red cells commonly number from 3,000,000 to 4,000,000, 
sometimes less, very rarely falling to the grade of pernicious anemia. 
They usually exhibit slight changes in size and moderate poikilocy- 
tosis. Nucleated red cells are rare, and if present are usually of 
normal size. The Hb-index is low. Leucocytes are usually dimin- 
ished in numbers, with relative lymphocytosis, and mast-cells are 
very scanty. The anemia usually continues for many years without 
aggravation, and most of the patients die of other diseases, although 
some develop pernicious anemia, and in some instances the condition 
is probably the forerunner of Banti's disease. 



266 SPECIAL PATHOLOGY OF THE BLOOD. 

This entire subject, especially in its clinical aspects, has been 
reviewed by Osier, throngh whose writings an introduction to the 
extensive literature may be secured. 

Bibliography. 
Pseudoleukemia. 

Askanazij. Ziegler's Beitrage, 1888, Bd. 3, p. 411. 

Banti. De 1' Anemia splenica, Florence, 1882. 

Barbier. Gaz. hebdom., 1894, No. 5. 

Baumgarten. Arbeit, a. d. Path. Instit. Tubingen, 1899. 

Berthenson. St. Petersburg med. Woch., 1879, p. 101. 

Biesiadecki. Wien. med. Jahrb., 1876. 

Billroth. Beitrage z. path. Hist., 1858, p. 158. 

Birch-Hirschfeld. ^Lehrbuch d. Path., 1895, p. 191. ^Ziemssen's Handb., 
Bd. 13, p. 100. 

Bonfils. Soc. Med. d'Observ., Paris, 1856. ? 

Brentano, Tangl. Deut. med. Woch., 1891, p. 588. 

Briihl Archiv. gen. de Med., 1891, I., II. 

Chvostek. Cited by Stengel. 

Cohnheim. Virchow's Archiv, Bd. 33, p. 451. 

Comhemale. Revue de Med., 1892, p. 540. 

Cornil, Ranvier. Man. d. Hist. Path., p. 251. 

Courmont. Archiv. de Med. Exper., 1892, No. 1, p. 115. 

Craigie. Path. Anat., 1828, p. 250. 

Delafield- N. Y. Med. Record, 1887, I., 425. 

Demange. These de Paris, 1874. 

Dietrich. Zeit. f. kl. Chir., Bd. 16, p. 376. 

Dreschfeld. Deut. med. AVoch., 1891, p. 1175. 

Dyrenfuth. Diss. Breslau, 1882, cited bv Grawitz. 

Eberth. Virchow's Archiv, Bd. 49, p. 63". 

Ebstein. ^Berl. klin. Woch., 1887, No. 31. ^ Deut. Archiv klin. Med., Bd. 
44, p. 389. 

Eisenmenger. Wien. klin. Woch, 1895, p. 505. 

Falkenthal. Diss. Halle, 1884, cited bv Ebstein. 

Fischer. .Irch. f. kl. Chir., Bd. 55, p. "^487. 

Fleischer, Penzoldt. Deut. Archiv klin. Med., Bd. 26, p. 368. 

Gaucher. These de Paris, 1882. 

Gilbert. Traite de Med. (Charcot), II., p. 528. 

GiUot. These de Paris, 1869. 

Gilly. These de Paris, 1886. 

Goldmann. Cent. f. Path., 1892, p. 665. 

Gowers. Pseudoleukemia (Reynolds' System of Medicine), 

Griesinger. Berl. klin. Woch., 1866, p. 212. 

Guillermet. These, Lyon, 1890. 

Hochsinger, Schiff. Viertelj. f. Dermat. u. Svph., 1877, 

Hodgkin. Med. Chir. Trans., 1832, p. 69. 

Jawein. Berl. klin. Woch., 1897, No. 33. 

Joseph. Deut. med. Woch., 1889, No. 46. 

Ranter. Cent. f. Path., 1894, p. 299. 

Kaposi. Oester. med Jahrb., 1885, p. 129. 

Kelsch. Bull, de Soc. Anat., 1873. 

Kossler. Jahrb. d. Wien. Krankenanstalten, 1893, p. 565. 

Kundrat. Wien. klin. Woch., 1893, pp. 211, 234, 

Laache. Die Anaemie, 1883. 

Lannois. Lyon Med., 1890, No. 34. 

Lannois, Lemoine. Rev. de Med., 1887, vol. ii. p. 257. 

Lowenbach. Arch. f. Derm. u. Syph., Bd. 48, p. 71. 

Lucke. Virchow's Archiv, Bd. 35, p. 524. 

Luzet. These de Paris, 1891. 

Monod, Terillon. Archiv. gen. de Med., 1879, vol. ii. pp. 34, 325. 

Mosler. Virchow's Archiv, Bd. 114, p. 461. 

Muller. Berl. klin. Woch., 1861. 



PSEUDOLEUKEMIA. 267 

Murchison. Trans. Path. Soc. London, 1870, p. 372. 

Musser. Trans. Assoc. Ainer. Phys., 1901, p. 638. 

Osier. Amer. Jour Med. Sci., vol. cxxiv. p. 751. 

Pel. Berl. klin. Woch., 1885, No. 1; 1887, No. 35. 

Pepper. .Aaier. Join-. Med. Sci., 1875, vol. Ixx. p. 313. 

Perrin. Bull, de Soc. Anat., 1861, p. 247. 

Ponfick. ^Virchow's Archiv, Bd. 50, p. 550. ^Qted by Steneel. 

Posselt. Wien. klin. Woch., 1895, p. 407. 

Potain. Semaine Med., 1887. 

Ramond, Picon. Archiv. de Med. Exper., 1896, p. 168. 

Reed. Jolins Hopk. Hosp. Rep.. a^oI. x. Nos. 3-5. 

Renvers. Deut. med. Woch., 1888, No. 37. 

Rothe. Inaug. Diss. Berlin, 1880. 

Runeberg. Deut. Archiv klin. Med., Bd. 33. 

Sahrazes. Soc. Anat. et Phvsiol. de Bordeaux, Feb. 8, 1892. 

Schehij-Buch. Deut. Archiv"^ klin. Med., Bd. 17. 

Schidz. Archiv f. Heilkunde, 1874, p. 200. 

Schmuziger. Archiv f. Heilk., 1876, p. 279. 

Sciola, Carta. Gaz. d. Osped., No. 5, 1894. 

Senator. Berl. klin. Woch., 1882, p. 533. 

Sevestre. Prog. Med., 1877, No. 34. 

Sharp. Jour, of Anat. and Physiol., vol. xxx. p. 59. 

Stengel. Twentieth Cent. Pract., a^oI. ii. p. 445. 

Sternberg. Zeit. f. Heilk., Bd. 19, p. 21. 

Strumpel. Archiv f. Heilk., 1876, Bd. 17, p. 547. 

Trousseau. Clinique Med. 

Velpeau. Lecons Orales de Clinique, T. III. 

Verdelli. Archiv. Ital. de klin. Med., 1894, T. 32, 4, p 595 

Virchow. Krank. Geschwulste, II. 

Waetzoldt. Cent. f. inn. Med., 1890, No. 45. 

Wagner. Deut. Archiv khn. Med., Bd. 38. 

Wende. Amer. Jour. Med. Sci., vol. cxxii. p. 836. 

Westphal. Deut. Archiv klin. Med., Bd. 51, p. 83. 

Wilkes. Guy's Hosp. Rep., 1856, p. 114. 

Woillez. Soc. med. d. Hop., 1856. 

Wunderlich. Archiv f. Physiol. Heilk., 1858, p. 123. 



CHAPTEK X. 

ANEMIA INFANTUM PSEUDOLEUKEMICA. SPLENECTOMY. 

ANEMIA INFANTUM (V. JAKSCH). 

Historical. In 1889-90 v. Jaksch described a form of infantile 
anemia clinically resembling leukemia, but failing at autopsy to show 
the visceral lesions of leukemia. 

The disease was said to be characterized by grave anemia, high 
and persistent leucocytosis, marked enlargement of the spleen, slight 
swelling of the liver and occasionally of the lymph nodes, and was 
to be distinguished from leukemia by the disproportionate size of 
the spleen as compared with that of the liver, by the more moderate 
leucocytosis, by the more favorable prognosis, and by the absence of 
leukemic infiltration of the viscera. 

Peculiar forms of grave anemia in infants had previously been 
described by Italian observers, Cardarelli, Somma and Fede, under 
the term ^^ infective splenic anemia. ^^ Hosier and Seuator also had 
long before recognized and described numerous cases of infantile 
anemia which they placed in an intermediate position between 
leukemia and pseudoleukemia. 

Shortly after v. Jaksch's first reference to this condition Hayem 
described a case in which the blood contained numerous nucleated 
red cells, many showing mitotic figures. The leucocytes were chiefly 
mononuclear, but the eosinophiles were increased. In Luzet's case 
nucleated red cells were not very numerous, but eosinophile cells 
w^ere increased and some mitotic leucocytes were seen. 

Thereafter reports of cases multiplied rapidly, so that in 1892 
Monti and Berggrun were able to collect sixteen cases, not including 
those of Hausse and Loos, and added four of their own. In recent 
years the knowledge of the condition has not been greatly extended, 
and opinions regarding its significance are still at variance. 

Etiology. The typical condition is usually limited to infants and 
children between one-half and four years of age. The majority of 
the reported cases have occurred in girls. Rachitis is of undoubted 
importance in the disease, since it was prominent in sixteen of the 
twenty cases of Monti and Berggrun. In the cases of severe rachitis 
reported by Hock and Schlesinger^ the changes in the blood resem- 
bled those of V. Jaksch's anemia, even when the spleen was not 
enlarged. Syphilis, chronic intestinal catarrh, and chronic tubercu- 
losis were found in other cases, collected by Fischl. 

An infectious origin was held for very similar cases as early as 
1880 by Cardarelli, and in 1887 by Somma and Fede. Later Mya 



AXEJIIA IXFAXTUM PSEUDOLEUKEMICA. 269 

and Trambasti, Toeplitz^ and Giantarco and Pianese, again main- 
tained the infectious nature of the malady. Recently Lowit reports 
finding the " hemameba leukemue magna " in one case. 

Pathological Anatomy. The changes in the viscera have been 
described principally by v. Jaksch (Eppinger), Luzet, Baginsky, 
Audeoud, and Rotch. 

The spleen is much enlarged, and usually rather firm. Histologi- 
cally the changes are those of simple hyperplasia of all elements^ 
while the sinuses contain an excessive number of leucocytes. Luzet 
found some mitotic normoblasts, but in his cases nucleated red cells 
were not numerous in the blood. Baginsky found many eosinophile 
cells in the spleen. Audeoud described extensive proliferative 
changes in the splenic follicles and pulp, gorging of sinuses with 
leucocytes, and occasional extravasations of blood. 

The liver, in the majority of cases, has been found moderately 
enlarged, usually less so than the spleen, and of uniform color and 
normal consistence. Luzet could not verify the claim that the liver 
is less affected than in leukemia, while in a case of the writer's the 
liver was quite as large as in fatal cases of leukemia in young chil- 
dren. Histologically there is an absence of leukemic infiltration, but 
Luzet found between the liver cords a considerable number of large 
cells (15^« to 25/i in diameter) which he regarded as progenitors of 
the red blood corpuscles. 

In a case of the writer's, examined in 1896, within the liver 
capillaries there were small collections of nucleated red cells and 
leucocytes, of which some of both were found in mitotic division, 
but the characters of leukemic infiltration were entirely wanting. 
The infiltration with these groups of small cells gave much the same 
appearance as the late fetal liver. In the fetal liver, however, these 
foci are composed almost exclusively of nucleated red cells. In one 
of Botch's cases also a similar condition was described. 

The lymph nodes were moderately enlarged in twelve of twenty 
cases, but in no degree comparable to the changes of leukemia. The 
marroiv was described by Luzet as diffusely reddened and moist, and 
as showing evidence of excessive multiplication of red cells. 

The Changes in the Blood. 

The red cells are always markedly diminished, v. Jaksch's case,, 
in which they numbered 820,000, showed exceptionally severe 
anemia, the majority of cases having 1,500,000 to 3,500,000 red 
cells. The ordinary changes of grave secondary anemia are to be 
noted in the red cells. Alt and Weiss found poikilocytosis very 
prominent, but this condition, together with megalocytes and micro- 
cytes deficient in Hb, are common to other anemias. 

An excessive abundance of nucleated red cells has been shown to 
be one of the most characteristic features of the blood of this condi- 
tion, in which they may be even more numerous than in leukemia. 
Yet they are not always present, in which case the disease bocomos 
difficult to distinguish from pseudoleukemia. Luzet, Alt, and M'oiss,. 



270 SPECIAL PATHOLOGY OF THE BLOOD. 

and others, have noticed that an unusual number of these cells are 
found in mitotic division. In well-marked cases the nucleated red 
cells may all be of normal size for this age, but in the graver stages 
of anemia megaloblasts reach a considerable proportion or a majority. 
The usual degenerative changes in the red cells of severe anemia 
have been described in several of these cases. 

The leucocytosis is an important characteristic. Usually the white 
cells number between 20,000 and 50,000, but in an apparently 
genuine case of Baginsky they varied between 122,000 and 40,000. 
In more typical instances the uniform persistence of the leucocytosis 
without marked variations has been somewhat peculiar. Some cases 
have recovered with diminishing leucocytosis. 

In most instances in which differential estimates are reported the 
mononuclear cells have been slightly in the majority. In apparently 
genuine cases (Rotch, Hock and Schlesinger"^) the mononuclear cells, 
large and small, formed 80 per cent., 84 per cent., and 75 per cent, 
of a greatly increased number of leucocytes (in one case 116,000), 
In other cases the polynuclear cells have been the more numerous. 
The proportion of eosinophile cells varies. Although considerably 
increased, up to 6 per cent. (Vickery), they do not reach either the 
proportions or numbers seen in leukemia. Myelocytes have been 
noted by Klein and in the more recent reports, but only in small 
numbers. In one of Yickery's cases 10 per cent, of myelocytes are 
reported among 22,000 white cells. Usually these cells are not so 
abundant as to suggest leukemia. 

Great variations in the size of the neutrophile leucocytes have 
been described, but cannot be regarded as a special character. The 
great variety of degenerative changes seen in all the blood cells, espe- 
cially in the leucocytes, has been very fully described and depicted 
by Engel. 

Significance of "v. Jaksch's Anemia." The attempt to deter- 
mine the true nature of the cases described under this term must be 
guided by the known characteristics of the blood of infants. The 
more important of these characters are : (a) The relative lymphocy- 
tosis ; (b) the more active leucocytosis excited hy chemotactic influences ; 
(c) the tendency to enlargement of the spleen in all chronic anemias of 
infants ; (d) the hyperemia of the marrow associated with rachitis ; 
(e) the facility with which blood formation in infants partially regresses 
toward the embryonal type. 

With these disturbing factors in view, it would appear that some 
of the reported cases of anemia pseudoleuhemica could better be 
classed as pernicious anemia by referring the peculiar leucocytosis to 
the special tendencies of infants' blood. Such a case is that of v. 
Jaksch, in which there were 820,000 red cells and 54,660 leucocytes 
of undetermined varieties. 

Other cases, like that of Eotch, with 1,311,500 red cells, 116,500 
leucocytes, 80 per cent, lymphocytes, enlarged lymph nodes, no 
autopsy, etc., might perhaps better stand as lymphatic leukemia with 
unusual proportion of nucleated red cells. Yet the present tendency 
is to accept too uncertain evidence in the diagnosis of lymphatic 



AXE.VIA INFANTUM PSEUDOLEUKEMICA. 271 

leukemia, and the writer agrees with Rotch in his classification of 
this case. One of Senator's cases also showed enlargement of lymph 
nodes and a ratio of 1 to 10 between leucocytes and red cells. 
Likewise Yickery's case, with 22,000 leucocytes, 35.8 per cent, 
lymphocytes, 10 per cent, myelocytes, and 6.2 per cent, eosinophiles, 
and no autopsy, may have been an early stage of myelogenous leu- 
kemia, but myelemia in infants, even if acute, ought to give more 
than 22,000 leucocytes and 10 per cent, of myelocytes, while if 
chronic its characters are usually unequivocal. The real nature of 
these cases must remain obscure in the absence of repeated and very 
complete examinations of ihe blood, and microscopic study of the 
viscera. 

Finally, it is possible that many of the cases are to be regarded as 
grave anemia icith leucocytosis of peculiar character. This view is 
supported by the occasional record of recoveries and of gradual trans- 
formations into grave anemia with ordinary leucocytosis (Monti, 
Berggrun). 

Nevertheless, in spite of the resemblance of many cases to perni- 
cious anemia, leukemia, or grave anemia with leucocytosis, there 
appears to be, ui the clinical history, in the morphology of the blood, 
and especially in the condition of the viscera, sufficient ground on 
which to separate, at least for the present, certain peculiar forms of 
chronic anemia in children from any of the above conditions. 

In the clinical history these signs are, chiefly, the chronic course, 
the frequent association with rachitis, syphilis, or chronic intestinal 
catarrh, the pronounced enlargement of the spleen, and the usual 
absence of distinct features of pernicious anemia, leukemia, or of a 
cause of leucocytosis. In the blood the changes are rarely such as to 
cause confusion with pernicious anemia, though the condition appears 
at times to precede pernicious anemia. While the acute cases with 
many lymphocytes or myelocytes may be indistinguishable from 
leukemia (one case of Luzet, XXV., having passed slowly into 
leukemia), in other more numerous instances the peculiar condition 
of the blood persists unchanged for months and shows no tendency 
to declare itself as leukemia. In the average case of grave secondary 
anemia the leucocytosis fails to show the peculiar characters of this 
condition. The excessive numbers of nucleated red cells and the 
very active multiplication of these cells and of leucocytes, as indi- 
cated by the large proportion of mitotic nuclei, and the abundance 
of myelocytes and eosinophile cells, or of large lymphocytes, are signs 
not necessarily connected with grave anemia in children, but here 
constitute a striking and distinctive blood picture. 

Considermg the cha,nges in the viscera, it is found that while the 
other features of the disease simulate pernicious anemia or leukemia, 
there are neither the leukemic infiltrations and hyperplasias nor the 
excessive iron-content of the liver, nor the megaloblastic changes in 
the marrow, of pernicious anemia. 

The writer is inclined to believe that the peculiar groups of 
mitotic red cells and leucocytes found in the hepatic capillaries of the 
single case which he has had opportunity to examine may indicate 



272 SPECIAL PATHOLOGY OF THE BLOOD. 

the essential nature of the condition. The presence of these cells 
shows that the liver had resumed or retained its fetal function of 
blood-cell formation. Similar groups of cells resembling leucocytes 
have been described by Kotch and similarly interpreted, but without 
mention of Hb-content or mitotic figures in the cells. Luzet also 
mentioned the presence of peculiar groups of cells in the liver. If 
these observations can be verified a specific anatomical condition will 
have been established for v. Jaksch's anemia, viz., the resumption 
of the liver under the influence of grave anemia or toxemia of its 
fetal function of developing red and possibly also white blood cells. 
The conditions would then differ from pernicious anemia in the 
absence of extreme megaloblastic changes in the marrow, and in 
the extension, rather, of megaloblastic red-cell formation beyond the 
marrow and into the next most available tissue, which is the liver. 
On this anatomical basis it would still be impossible to explain the 
frequent presence of many lymphocytes or myelocytes which, how- 
ever, may be referred to the coincident affection of lymphoid tissues, 
especially of the marrow, a tissue which in this disease has as yet 
received inadequate attention. 

In a case observed by the writer in 1896 the patient was a markedly rachitic 
infant of twenty months. The spleen extended three inches below the costal 
border. The liver was considerably enlarged. The lymph nodes were not 
enlarged. The red cells numbered 1,820,000, about 10 per cent, of which were 
pale megalocytes. Nucleated red cells were extremely abundant and usually 
of normal size. Hb not taken. The leucocytes numbered 48,000, of which 22 
per cent, were small lymphocytes, 34 per cent, large lymphocytes, 3 per cent, 
myelocytes, 88 per cent, polynuclears, 3 per cent, eosinophiles. 

The spleen was the seat of uniform hyperplaeia of pulp cells, while the 
follicles were much reduced in size and number. Throughout the pulp there 
were numerous small collections of small cells with compact or mitotic nuclei. 
Many of these were nucleated red cells. Mitotic leucocytes were not identified. 
There was beginning increase of connective tissue and the sinuses were often 
obliterated. Eosinophile cells were very abundant. The liver exhibited numer- 
ous small intracapillary foci of cells, many of which contained mitotic nuclei. 
Of these the majority were nucleated red cells, others were much larger and 
granular. Occasionally they appeared fused together in one cell mass, resem- 
bling the multinuclear masses of Luzet. These groups of cells resembled the 
foci of nucleated red cells of the embryonal liver, but were much less numerous. 
The liver cells were not fatty. 

The marrow of the femoral shaft was cellular throughout, no fat cells being 
found in this situation, which, in normal subjects of this age is at least partly 
fatty. There was general hyperplasia of cellular elements, but the cells were 
not densely packed as in leukemia. The islands of nucleated red cells were 
very numerous, these cells being distinctly in excess. Many mitotic leucocytes, 
with granular protoplasm were identified. The sinuses were obliterated. 
Eosinophile cells were not overabundant. The condition of the spleen, liver, 
and marrow indicated that excessive demands were being made upon the blood- 
forming organs, and that these demands were being met by the marrow, the 
liver, and probably also by the spleen. 

Bibliography. 
Anemia Infantum. 

Alt, Weiss. Cent. f. med. Wissen., 1892, Nos. 24-25. 
Audeoud. Revue med. de la Suisse Rom., 1894, p. 507. 
Baginskij. Archiv f . Kinderheilk., 1892, Bd. 13, p. 304. 



SPLENECTOMY. 273 

Cardarelli. Atti d. primo Cona;. Pediatr., Naples, 1891. 

Engel. Virchow's Archiv, Bd. 135, p. 369. 

Fede. Atti d. primo Cong. Pediatr., Naples, 1891. 

Fischl. Zeit. f. Heilk., 1892, Bd. 13, 277. 

Gianturco, Pianese. Gaz. d. Clin., Naples, 1892, III., p. 305. 

Hausse. Diss. Miinchen, 1890. 

Hayem. Gaz. des. Hop., 1889, No. 30. 

Hock, Schlesinger. ^ Beitrage ziir Kinderiieilk., Wien., 1892. ^ Cent, f klin. 
Med., 1891. 

V. Jaksch. "Wien. klin. Woch., 1889, Nos. 22-23. Prager med. Woch., 1890, 
No. 22. 

Klein. Beri. klin. Woch., 1890, No. 31. 

Loos. Wien. klin. Woch., 1891, p 26. 

Lbwit. Die Leukaemie als Protozoeninfec. Wiesbaden 1900. 

Luzet. Archiv. gen de Med., 1891, I., p. 579. These de Paris, 1891. 

Monti, Berggrun. Die chron. Anaemie, etc., Leipzig, 1892. 

Mosler. Cited by Senator. 

Mya, Tramhusti.^ Lo Sperimentale, 1892. 

Rotch. Pediatrics, Philadelphia, 1897, p 359. 

Senator. Beri. klin. AVoch , 1882, p. 533. 

So7nma. Allg. Wien. med. Zeit., 1891, Nos. 4-11. 

Toeplitz. Jahrbuch f. Kinderheilk., Bd. 33, p. 367. 

Vickery. Med. News, 1897, vol. Ixxi. p. 731. 



SPLENECTOMY. 

The effects of splenectomy upon man are usually the combined 
results of severe hemorrhage, or pre-existing anemia, of the loss of the 
function of the organ, and very often of intravenous infusion prac- 
tised immediately after the operation. 

How much of these effects are referable solely to the loss of the 
organ can better be determined by comparing the blood changes 
following splenectomy in animals with those observed in the human 
subject. 

Effects of Splenectomy in Animals. 

Mosler was one of the first to study the effects of splenectomy upon healthy 
dogs. He found a diminution of red cells, persisting for several months, but 
no changes in the leucocytes. The blood-forming function, then regarded as 
inherent in thespleen, he believed to have been transferred to the marrow, in 
which tissue he found changes comparable to those of leukemia. The chief 
permanent chemical alteration he found to be a loss of iron. Malassez found 
the oligocythemia to persist only one month, while the Hb remained deficient 
much longer. Zesas found in rabbits a marked leucocytosis, reaching a maxi- 
mum in the tenth week, when the red cells begin to diminish. The blood was 
restored to the normal six months after the operation, Winogradoff" found 
that the red cells in dogs diminish for 200 days, and many megalocytes appear. 
In the second year smaller cells reappear, and the total number gradually be- 
comes normal. In two of three dogs there was considerable leucocytosis. 
Diminution of specific gravity and of Hb was constantly noted. The lymph 
nodes of the animals w^ere found to be smaller, and the marrow hyperemic. 
Gibson found the maximum diminution of red cells sixty days after splenec- 
tomy (three dogs). Pronounced leucocytosis was observed the day after the 
operation. The restoration of the blood required six months. 

More recently Kourloff followed the course of the leucocytosis of splenec- 
tomy, finding in the first year following the operation varying grades of lym- 
phocytosis, the proportion of these cells rising from 30 up to 60 per cent. The 
proportion of granular leucocytes fell from 40 or 50 per cent, to 20 per cent., or 
less. The number of large mononuclear cells did not change, indicating that 
the spleen cannot be considered as their place of origin. During the second 

18 



274 SPECIAL PATHOLOGY OF THE BLOOD. 

year a prominent alteration of the blood was a marked eosinophilia, while in 
this period the lymphocytes fell to the normal proportion. 

Emilianoff demonstrated in splenectomized dogs a slight diminution of red 
cells and an extreme lencocytosis marked by an initial loss of small cells, and 
a sudden increase of larger (polynuclear) cells. Vulpius also observed in 
several rabbits a moderate lencocytosis lasting not longer than nine weeks, and 
a loss of 20 per cent, in the number of red cells, which were restored within 
five to six weeks. 

It has therefore been shown, by the above observers among others^ 
that splenectomy in animals is followed by moderate reduction in 
red cells lasting from one to twelve months, by relatively greater 
loss of Hb more slowly restored, and in some cases by the appearance 
during the first year of megalocytes. 

Lencocytosis follows the operation, but its extent and duration are 
very variable. A polynuclear lencocytosis is observed during the 
first days or weeks, followed by relative or absolute lymphocytosis 
during the first year, while during the second year distinct eosino- 
philia may be observed. 

With these changes in the blood are associated a marked cellular 
hyperplasia of the marrow, approaching at times that of leukemia^ 
and often also affecting the lymph nodes. In the swollen nodes an 
excessive number of nucleated red cells have been found by Wino- 
gradoff, Tizzoni, Gibson, Kourloff, and Grunberg. 

Splenectomy in Man. 

The most marked changes in the blood following splenectomy in 
man are seen in those cases in which the organ has been removed 
for rupture or idiopathic enlargement. Successful cases are recorded 
by Czerny,^ Regnier, Hartley, McBurney, and others. In Czerny's 
case of idiopathic enlargement (1500 grm.) the Hb fell to 56 per 
cent., while the red cells were very slightly reduced and reached 
over 5,000,000 within a month ; but four years later the patient, for 
reasons not stated, was found to have only 3,300,000 red cells with 
85 per cent, of Hb. The lencocytosis was very marked, reaching 
70,000 within a week and persisting for at least eight weeks. 

In Regnier's case of rupture of spleen with severe hemorrhage 
the Hb fell to 20 per cent., rising gradually to 80 per cent, in the 
eighth week. The red cells, falling to 2,500,000, rose to 4,700,000 
by the eighth week. An acute lencocytosis, 25,000, appeared soon 
after the operation. One month later the polynuclear cells had 
been largely replaced by an equal number of lymphocytes. Nucleated 
red cells and eosinophiles were scarce. 

Hartley's case (examined by the writer) was complicated by infu- 
sion, and possibly by pre-existing malaria. The anemia on the fourth 
day was profound ; the lencocytosis was extreme, estimated roughly at 
75,000 cells, of which 77 per cent, were polynuclear. Many " spleno- 
cytes " and a moderate number of myelocytes with deficient neutro- 
phile granules, and a few normoblasts, were present, so that the 
blood strikingly resembled that of leukemia. At the end of three 
weeks the young patient's blood had greatly improved, and the 



SPLENECTOMY. 275 

leucocytes were normal. After three months the only abnormality 
was the presence of a few moderate-sized megalocytes and an 
apparent deficiency of neutrophile granules. Later examinations, 
extending over three years, failed to show at any time an absolute in- 
crease of either lymphocytes or eosinophils or any persistent anemia. 

In McBurney's case the Avriter found the anemia and the resem- 
blance to leukemic blood even more pronounced. The same prompt 
improvement followed, and six months later the blood was practically 
normal. 

After splenectomy for various other general indications, not includ- 
ing malaria and leukemia, rather variable results have been noted. 
In the cases collected by Vulpius, Hartley, and Litten, and reviewed 
by various authors, the w^riter finds a general resemblance of the 
blood changes when reported to those described after experimental 
splenectomy. The grade of anemia and the period required for the 
restoration of the blood seem to vary with the general condition of 
the patient and the circumstances of the operation. Dominici 
describes a case in a tuberculous subject in whose blood, twelve days 
after the operation, a very large number of nucleated red cells began 
to appear, 9800 j^er c.mm. having been counted at one time. After 
three weeks they disappeared. 

In the majority of the cases of splenectomy for wandering spleen 
and other conditions not seriously affecting the patient^s health, the 
blood was described as normal before and after the operation, but in 
some the usual reduction of red cells and leucocytosis have been 
observed. The slight changes normally noted are probably referable 
to the effects of the laparotomy, as Hartmann and Vaquez found that 
after every such operation there is slight anemia and leucocytosis. 

The malarial spleen has been excised by many surgeons with 
favorable results. Jonnesco, who reports a series of cases, found a 
prompt increase of red cells after a temporary diminution (500,000 
to 2,000,000) and a somewhat persistent leucocytosis (15,000 to 
30,000). The operation effected a prompt cure of long-persistent 
cachexia. Similar favorable results were obtained by Hartley, 
Vulpius, and others. 

In leukemia Hagen collected forty-two extirpations of the spleen 
with four recoveries from the operation, and to these must be added 
one case of Richardson, reported by Warren, in which the patient 
recovered while the effect on the blood remained suh judice. One 
case survived thirteen days, another eight months, and a third, in 
which tlie diagnosis must be doubted (Franzolini, 1882), was reported 
cured. In two genuine cases the operation was followed by steady 
diminution of red cells and increase of leucocytes (Bardenhauer, 
Burckhardt). 

Visceral Changes following Splenectomy. Enlargement of 
lymph nodes has been observed after splenectomy in man by Czerny,^ 
Kocher, Lennander, and Regnier. In Regnier's case the enlarge- 
ment of the nodes was associated with lymphocytosis. The marrow 
was examined by Regnier four Aveeks after the splenectomy nnd 
found very hyperemic. There had been marked anemia in this case. 



276 SPECIAL PATHOLOGY OF THE BLOOD. 

Resume. In comparatively healthy subjects splenectomy has often 
been performed without affecting the blood more than does any other 
laparotomy. 

In many graver cases the loss of blood and the shock of the opera- 
tion give rise to a considerable grade of secondary anemia. The red 
cells are, in favorable cases, restored in one to three months, but in 
less favorable cases there may be more persistent anemia. The 
restoration of Hb seems in some cases to fall behind the improve- 
ment in cells rather more than in most secondary anemias. The 
operation is usually followed by considerable polynuclear leucocytosis 
(15,000 to 50,000), which commonly persists for two to six weeks, 
but may continue for months, in which case the polynuclear cells 
may be largely replaced by lymphocytes. Eosinophilia has been 
observed in a few cases during the second and third years. 

In traumatic cases suffering from large hemorrhages, splenectomy, 
especially when complicated by infusion, may lead to very profound 
anemia, marked by extreme loss of red cells, the presence of many 
very large, pale, sometimes polychromatic, and dissolving red cells, 
nucleated red cells, and to a high grade of leucocytosis. Among 
the leucocytes there may be a considerable proportion of large, pale, 
mononuclear cells and myelocytes, so that the blood resembles that of 
acute leukemia. This condition, however, is transitory and the blood 
may improve rapidly. Leukemia and the amyloid spleen are con- 
traindications to splenectomy. In other conditions the choice of 
operation may depend entirely upon the general condition of the 
patient. Beyond a moderate persistent leucocytosis or lymphocytosis, 
and possibly a slight delay in the restoration of Hb, there are no 
specific effects known to follow splenectomy in man. 

Bibliography. 

Splenectomy. 

Bardenhauer. Deut. Zeit. f. Chir., Bd. 45, p. 181. 

Burckhardt. Archiv f. klin. Chir., Bd. 43, p. 446. 

Czerny. ^ Cited by Vulpius. ^ "vvien. med. Woch., 1879, p. 333. 

Do772mici. Compt. Rend. Soc. Biol., 1898, p. 1193. 

Emilianoff. Archiv des Sci. Biol., St. Petersburg, Bd. 2, No. 2. 

Franzolini. Gaz. med. Ital., 1882, Guil. 

Gibson. Jour, of Anat. and Physiol., 1886, vol. xx. p. 674. 

Grunberg. Diss. Dorpat, 1891. 

Hagen. Archiv f. klin. Chir., Bd. 62, p. 188. 

Hartley. Med. News, 1898, vol. Ixxii. p. 417. 

Hartman, Vaquez. Compt. Rend. Soc. Biol., 1897, p. 126. 

Jonnesco. Archiv f. sci. Med. (Bucharest), 1897, p. 301. 

Kocher. Cent. f. Chir., 1889, p. 14. 

Kourloff. Wratch, 1889, 1892, cited bv Ehrlich, Die Anaemie. 

Lennander. Wien. klin. Woch., 1893, No. 30. 

Malassez. Gaz. med. de Paris, 1878, p. 317. 

McBurney. N. Y. Med. Record, vol. liii. p. 601. 

Hosier. Leukemia, 1872. 

Regnier. Berl. klin. Woch., 1893, p. 181. 

Tizzoni. Archiv. Ital. de Biol., 1882, T. 1. 

Vulpius. Beitrage zur klin. Chir., 1894, Bd. 11. 

Warren. Annals of Surgery, vol. xxxiii. p. 513. 

Winog/odoff. Cited by Laudenbach, Archiv. de Physiol., 1896, p. 724. 

Zesas. Langenbeck's Archiv, Bd. 28, p. 157. 



PAET III. 

THE ACUTE mFECTIOUS DISEASES. 



INTRODUCTORY SECTION. 

THE BLOOD IN FEVER. 

While all observers have agreed that the blood in fever suffers a 
reduction in red cells, it still remains a matter of doabt whether a 
febrile process alone actually destroys red cells or only causes them 
to be unequally distributed in the body. 

The theory of unequal distribution of red cells in the acute fevers 
is supported by a variety of observations. Maragliano demonstrated 
a contraction of arterioles during the height of a febrile process, fol- 
lowed by dilatation during defervescence, and he was able to verify 
these results by watching the effects of antipyretics. Breitenstein 
found an excess of red cells in the livers of heated animals coincident 
with a deficiency in peripheral vessels, while Naunyn under the 
same conditions could find no evidence of destruction of red cells. 
Increase in specific gravity of the blood was demonstrated by Stein, 
with rising temperature, followed by lowering of gravity in defer- 
vescence, Reinert believes that excessive loss of fluids diminishes 
the volume of blood during the height of the fever, while retention 
of fluids results from lower blood pressure and heart weakness after 
defervescence. Tumas believes that the blood in fever may be re- 
duced in bulk as well as in proportion of red cells. 

In favor of the view that the red cells are destroyed in fever is 
the demonstration of an excess of potassium (Salkowski) and of 
hydrobilirubin (Gerhardt, Hoppe-Seyler) in the urine. Yet Bunge 
has shown that the red cells, which are very rich in potassium, may 
take up and discharge large amounts of this element without them- 
selves being destroyed. In pure types of experimental pyrexia 
Naunyn and others have found no solution of Hb in the blood serum 
and no evidences of destruction of red cells. Werhowsky, however, 
exposed rabbits to a temperature of 38.5° to 40° C. for two to 
twenty-nine days and found a steady diminution, reaching 30 per 
cent, of Hb, followed by progressive loss of red cells, moderate lenco- 
cytosis, and deposits of hemosiderin in the marrow and spleen. 
Similar indications were obtained long ago by Mobitz in septic 
animals whose blood at first showed from day to day considerable 
variations in the red cells, but eventually a permanent loss. 



278 THE ACUTE INFECTIOUS DISEASES. 

These results leave no doubt of the capacity of prolonged fever to 
destroy red cells, but the length of time required furnishes opportunity 
for factors other than pyrexia to intervene. Consequently Lowit^ con- 
cludes that the real nature of the oligocythemia in the early febrile 
process is still doubtful. 

Fever is usually accompanied by marked disturbance of the coagu- 
lation of the blood, which has sometimes been found increased, at 
others diminished or entirely inhibited. From the studies of Schmidt 
and his pupils it has been shown that in septic fever coagulation is 
diminished at an early stage and increased at another later stage. 
The variations depend, according to Bojanus, upon changes in the 
quantity either of fibrinoplastic substances or of fibrin ferment, and 
are connected witli the presence of dissolved Hb in the plasma. In 
non-febrile pyrexia, insolation, the coagulability of the blood is lost. 

Changes in Chemical Composition. A progressive loss of albu- 
mins of the blood in febrile diseases has been noted by many 
observers, but it is not yet known whether the loss is referable to 
the pyrexia or to other associated factors. Rather favorable clinical 
conditions for determining the effects of fever were found by Stejskal 
in a case of intermittent Ebstein's disease, in which during the febrile 
intervals he demonstrated a decrease of albumins and diminution of 
ash in the whole blood, in the serum, and in the red cells. 

While there is good reason to believe that the less diffusible 
globulin should suffer less than the albumin, as Gottschalk claims 
to have found in some instances, yet Limbeck and Pick found that 
no general rule could apply to variations in the globulin of the blood 
in infectious diseases. A contrary conclusion also was reached by 
Emmerich and Tsuboi, w^ho found the globulin of the blood to 
diminish when rabbits are being immunized against hog-cholera. 

Resistance of Red Cells in Fever. A diminished resistance of 
the red cells and increased isotonic tension of the plasma were 
demonstrated by Maragliano in severe anemia, and by Celli and 
Guarnieri in various fevers, while the morphological characters 
which indicate this change in the red cells have been described by 
Maragliano, Gabritschewsky, and Grawitz. Yet the resistance of the 
red cells is not found diminished in all fevers and may, as Limbeck^ 
has shown, be at times increased. While Hamburger has shown 
that the resistance of the red cells depends principally upon the 
osmotic tension of the plasma, Demoor refers the low resistance in 
fever to the presence in the blood of bacterial toxins and of excess 
of CO2, while Lowif^ connects it more closely with changes in the 
vessel walls. 

Febrile Hydremia. A marked diminution of the albumins of the 
plasma has been demonstrated in many infectious diseases by Ham- 
marschlag, Limbeck,^ Biernacki,i Wendelstadt, and others, and has 
been referred not to increase in the total bulk of water in the blood, 
but to destruction of albumins in the febrile process. Herz believes 
further that the febrile hydremia is characterized also by swelling of 
the red cells with corresponding oligoplasmia, and Limbeck and 
Steindler found the volume of the serum in three healthy subjects 



INTBOD UCTOR Y SECTION. 279 

to average 72.6 per cent., while in eight acute febrile cases it fell to 
an average of 54.8 per cent. On the other hand, Pfeiffer denies 
that the red cells swell in febrile diseases, finding rather that they 
shrink, and Biernacki denies the existence of any uniform febrile 
hydremia. The conclusions of each of the above observers appear 
to be justified by their results, and their conflicting opinions must 
be referred to technical errors or to particular conditions existing in 
the subjects of their study. 

Alkalescence. Abundant sources of acid metabolic products are 
believed to exist in fever as a result of imperfect oxidation of albu- 
mins and the formation thereby of fatty and lactic acids, as well as in 
the development of acids as a result of bacterial growth. Numerous 
observations, also, by Senator, v. Jaksch, Kraus, Klemperer, and 
others, have apparently shoAvn by different methods that febrile 
processes are regularly marked by diminished alkalescence of the 
blood. Yet Minkowski has from the first pointed out that at the 
height of the fever the loss of alkalescence is not proportional to the 
pyrexia. Limbeck and Steindler in a large series of febrile subjects 
found in both blood and serum variations in alkalescence quite 
within normal limits. 

On the other hand, Lowy and Richter, using a special method 
which they claim to be more reliable than others, find that in a cer- 
tain period of febrile processes corresponding to the stage of hypo- 
leucocytosis the blood shows an increase and not a decrease of alka- 
lescence. The cause of this condition is not yet explained, but 
Lowy's results have been verified by Lowit, Biernacki,^ and Strauss. 

Important contributions to the subject were made by Fodor and 
Rigler. These observers found that the serum of rabbits infected 
with anthrax at first shows an increase of alkalescence, but after 
twenty-four hours a rapid and marked diminution. With rabies the 
alkalescence diminished from the first. Between the quantity of 
diphtheria toxin injected and the final loss of alkalinity therefrom 
they found a parallel. Injections of vaccine increased the alkales- 
cence for seven to eight days, of diphtheria antitoxin for only forty- 
eight hours. Since the alkalinity of the serum-ash did not vary 
with that of the serum they concluded that the property depends on 
the presence of organic substances. Other important studies of the 
alkalescence of the blood by Cantani, Calabrese, and others have 
shown that the important variations in the quality of the blood are 
dependent less upon fever than upon other obscure chemical processes. 

Lowif concludes that the alkalescence of the blood may he increased 
at one time and diminished at another period of an infectious disease, 
that this property is not dependent in any large measure upon the leuco- 
cytes, and that its significance is still unexplained. 

Action of Bacteria and Their Products on the Blood. ]N[any 
of the phenomena classed among the effects of fever on the blood 
can be directly traced in part to the action of bacteria and bacterial 
products which are the exciting causes of the febrile process. 

Bouchard has deuionstrated for the bodies of bacillus pyocyancus, 
and Gley and Charrin for their filtered products, a vasoconstricting 



280 THE' ACUTE INFECTIOUS DISEASES. 

action, and therefore a tendency to concentrate the blood. An 
increased flow of lymph and probably a similar concentrating effect 
upon the blood has been shown to follow the injection into animals 
of peptone and animal extracts, by Heidenhain ; of tuberculin, 
pyocyanin, pneumotoxin, by Gartner and Romer. Rapid variations 
in the gravity of the blood have, in Grawitz's^ hands, followed the 
injection of cultures of cholera, diphtheria, and pyogenic organisms. 
Small doses of toxins of various bacteria were found by Bianchi and 
Mariotti to increase the isotonic tension of the blood quite beyond 
normal limits, while large doses of many germs or even small injec- 
tions of baGiUus typhosus had the opposite effect. 

Specific bacterial products, toxalbumins, bacterioproteins, and 
ptomains are believed by most observers to be the active agent in 
the destruction of the albumins of blood and tissues in infectious 
diseases, acting at times without the accompaniment of fever (Miiller). 

As a specific effect of the chemotactic action of bacteria and their 
products upon the white blood cells there is the whole series of 
phenomena of leucocytosis, the significance of which is considered in 
another section. 

Conclusions Regarding the Blood in Fever. From the fore- 
going brief review it will be seen that the changes in the blood in 
fever form an extremely complex subject, about which our knowledge 
is still rather fragmentary. The same phenomena have been encoun- 
tered in different lines of investigation and attributed to different 
single factors, though probably referable to many. While some 
main facts are rather distinctly apparent, other questions must remain 
undecided until fully adequate technical methods are devised. 

Decrease or relative increase in the proportion of 7'ed cells, but 
ending always in a loss in their total numbers, must be accepted as 
accompanying all cases of pyrexia, although requiring some time to 
become clearly apparent. 

Coagulability varies in different stages of febrile diseases, but is 
not clearly connected with the pyrexia as such. 

The progressive loss of albumin of the blood is probably essentially 
connected with the febrile process, but occurs in increased degree 
when the fever is of infectious origin. 

Febrile hydremia is an accidental condition which may or may not 
occur as a result of the loss of albumins of the blood. Diminished 
resistance of red cells occurs in the majority of fevers, and depends on 
a variety of factors. Variations in alkalinity are frequent and con- 
siderable in fever, but are not proportional either to the height of the 
temperature or to the toxic condition of the blood. 

BiBLIOGEAPHY. 

Blood in Fever. 

Bianchi, Mariotti. Wien. med. Presse, 1894, No 36. 

Biernacki. "■ Zeit. f. klin Med., Bd. 24. ^ i^id., Bd. 31, p 312. 

Bojanus. Inaug. Diss. Dorpat, 1881. 

Bouchard. Lecons sur les Autointoxications, Paris, 1887 

Breitenstein. Archiv f . exper. Path., Bd. 18, p. 42. 

Bunge. Zeit. f. Biol., Bd. 9, p. 129. 



lyTB OB UCTOR Y SECTION. 281 

Calabrese. Policlinico, 1896, fasc. 1, 2. 
Cantajii. Cent. f. Bact., Bd. 20, p. 556. 
Celli, Guarnieri. Fort. d. Med., 1889, No. 14. 
Demoor. Jour. med. de Bruxelles, 1896, No. 36. 
Emmerich, Tsuhoi. XI. Cong. f. inn. Med., 1892, p. 202. 
Fodor, Rigler. Cent. f. Bact., Bd. 21, p. 134. 
Gahritscheicsky. Archiv f. exper Path., Bd. 28, p. 83. 
Gartner, Bomer. Wien. klin. Woch., 1892, No. 2. 
Gerhardt. Ueber Hvdrobilirubin, Diss. Berlin, 1889. 
Gley, Charrin. Cent. f. Bact., 1894, p. 688. 
Gottschalk. Zeit. f. phvsiol. Chem., Bd. 12, cited by Limbeck. 
Grawitz. ' Zeit. f. klin. Med., Bd. 22, p. 411. 
Hamburger. Virchow's Archiv, Bd. 140, p. 503. 
Hammarschlag. Zeit. f. klin. Med., Bd. 21, p. 475. 
Herz. Virchow's Archiv, Bd. 133. 
Hoppe-Seyler. Virchow's Archiv, Bd. 124, p. 30. 
V. Jaksch. Zeit. f. klin. Med., Bd. 13. 
Kraiis. Zeit. f. Heilk., Bd. 10. 

Limbeck. ^ Klui. Path, des Blutes, 1896, p. 158. ^ p^ager med. Woch., 1893, 
Nos. 12-14. 

Limbeck, SteindJer. Cent. f. inn. Med., 1895, p. 649. 

Lowit. ' Die Lehre v. Fieber. ^ ibid., p. 151. ^ Ibid., p. 164. 

Lowy, Richter. Deut. med. Woch., 1895, No. 33. 

Maragliano. Berl. klin. Woch., 1887, No. 43. 

Minkowski. Archiv f. exper. Path., Bd. 19, p. 215. 

Mobitz. Inaug. Diss. Dorpat, 1883, cited bv Lowit. 

Muller. Zeit. f. klin. Med., Bd. 16, p. 496. *' 

Naunyn. Archiv f. exper. Path., Bd. 18, p. 81. 

Pfeijjer. Cent. f. inn. Med., 1895, No. 4. 

Reinert. Zahliing d. Blutkorp, p. 174. 

Schmidt. Pfliiger's Archiv, Bd. 11, pp. 291, 515. 

Senator. Untersuch. u. cl. fieberhaften Process, Berlin, 1873. 

Stein. Cent. f. klin. Med., 1892, No. 23. 

Stejskal. Zeit. f. khn Med., Bd. 42, p. 309. 

Strauss. Zeit. f. klin. Med., 1896, Bd. 30, p. 315. 

Tumas. Deut. Archiv klin. Med., Bd. 41, p. 323. 

Wendelstadt. Zeit. f. klin. Med., Bd. 25. 

Werhowsky. Cong. f. inn. Med., 1895, p. 345. 



CHAPTEE XI. 

PNEUMONIA. DIPHTHERIA. 

PNEUMONIA. 

The gross characters of the blood in pneumonia were accurately 
described by Piorry, who noted the prompt and firm clotting due to 
excess of fibrin, while the distinct crusta 'phlogistica, most marked 
about the seventh or eighth days, was the earliest recorded observa- 
tion concerning the leucocytosis of this disease. Fibrin has since been 
shown to be abundant in nearly all cases of pneumonia, and very 
much increased in the great majority. The excess often continues 
beyond defervescence. In very severe cases without leucocytosis, 
fibrin is usually deficient (Turk^). 

The total volume of blood is probably somewhat reduced in severe 
cases of pneumonia, owing to the concentration which occurs in fever, 
from cyanosis, and from the loss of cells and plasma in the exudate. 
Evidences of this concentration have accumulated from several sources, 
among which are : the increase in specific gravity during the height 
of the process (Monti, Berggrun), and the persistence of a high pro- 
portion of red cells and Hb which usually continues until the crisis, 
after which there is a rapid decline in the quality of the blood. 

Large exudations into the lungs are believed by Bollinger to 
reduce the quantity of blood to such an extent that oligemia may 
usually be noted at autopsy. In 65 per cent, of his cases marked 
diminution of blood was thus noted at the postmortem examination, 
a loss which was fully explained by the extent of the exudate, which 
averaged over 1000 grm. in weight. 

The Red Cells. Although destruction of red cells undoubtedly 
occurs in the disease, as shown by the increased excretion of hydro- 
bilirubin, and the occasional appearance of jaundice, yet the propor- 
tion of red cells remains high during the active febrile period, when 
this destruction is taking place, to diminish only when the tempera- 
ture begins to fall. This result can be referred only to the concen- 
trating effects of fever, exudation, and local vasomotor phenomena, 
and is to be seen in other infectious fevers. 

In spite of these complicating factors the red cells usually show a 
slight but steady decline during the course of the fever, as shown by 
the reports of Sorensen, Boeckman, Halla, Tumas, Sadler, and others. 

Slight polycythemia (maximum 7,000,000) frequently appears in 
the reports of Sadler, while Sorensen observed an increase of red 
cells during the febrile period in one case. The decrease of red cells 
often occurs suddenly with the crisis, Tumas reporting one case with 
a fall of 600,000 on the day of defervescence. The diminution con- 



PXEUMONIA. 283 

tinues for a very variable period depending upon somewhat complex 
factors, bat commonly ceases within ten to fourteen days, or in mild 
cases much sooner. 

The grade of anemia established is usually not very marked. In 
many recorded estimates the loss of cells did not exceed the limit of 
error. A loss of 500,000 to 1,000,000 is not uncommon, while a re- 
duction of 2,000,000 cells is recorded by several observers. Such 
changes in the red cells, however, must be interpreted with great 
caution. There was, for instance, a loss of 2,000,000 cells in one of 
Sadler^s cases, yet no anemia was established, as the blood had been 
concentrated and the lowest count was 5,100,000. 

Morphological changes in the red cells are usually slight. Poly- 
chromasia is seen in the sev^ere cases only. 

Nucleated eed cells were present in seven of Turk's eighteen 
cases. These were usually normoblasts, occasionally megaloblasts. 
The cases were all very severe, but only one of the seven was fatal. 
A similar phenomenon may occur in other severe infections. 

The Hb suffers considerably more than the red cells, being almost 
invariably reduced after defervescence, but in the absence of compli- 
cations seldom falling below 65 per cent. 

Chemistry. The specific gravity was found to remain normal or 
to distinctly increase during the febrile period in nine children studied 
by Monti and Berggrun.^ The albumins of the blood were slightly 
diminished, while those of the serum were normal or increased in 
seven cases reported by v. Jaksch.^ 

The toxicity of the blood serum was found much increased in pneu- 
monia and other infectious diseases by Albu, who locates the poisonous 
principle in the albumins of the serum. 

Leucocytes. Leucocytosis appears in the great majority of cases 
of pneumonia, failing only in very mild attacks and in very severe 
infections with feeble reaction and bad prognosis, and when some pre- 
existing conditions have already excited leucocytosis or debilitated 
the system. In leukemia a complicating pneumonia reduces the 
leucocytes, while the onset of pneumonia in the course of some infec- 
tious diseases is not always traceable in the blood. 

Although the leucocytosis of pneumonia was noted by Virchow, 
Nasse, and other early writers, its closer study was begun by Sorensen 
in 1876, and continued by Boeckman, Halla, Tumas, Hayem, and 
Limbeck.^ 

Even Boeckman (1881) orathpred from the literature that most febrile diseases 
are accompanied hj leucocytosis, and that typhoid fever and malaria are ex- 
ceptions to the rule. Halla noted that the leucocytosis is not proportional to 
the fever, having encountered three cases without leucocytosis, all fatal. 
Hayem and Limbeck followed the course of the leucocytosis over considerable 
periods, pointed out relations between the grade of leucocytosis and the 
severity of the disease, discussed the time and manner of its disappearance, 
and reported other fatal cases without leucocytosis. 

Limbeck's study was especially minute and he was able to detect a fall in 
the leucocytosis some hours before the crisis, and to note the absence of any 
change during pseudocrises. He drew the important general deduction that 
leucocytosis precedes and is a part of the inflammatory exudate, and that non- 
exudative diseases are unaccompanied by leucocytosis. Rieder, in 189l\ was 



284 "^^HE ACUTE INFECTIOUS DISEASES. 

probably the first to demonstrate that the leucocytosis of pneumonia is not 
determined by the height of the fever or the extent of the exudate, but de- 
pends upon the intensity of the infection and the degree of resistance of the 
subject, and this view was fully supported shortly afterward in the writer's 
series of cases. 

Since Limbeck's study the leucocytosis of pneumonia has been a favorite 
field of investigation, so that an extensive literature in many languages has 
accumulated, and many interesting and important details have been added to 
the knowledge of the subject. 

Course of the Leucocytosis. Leucocytosis appears very early in 
the course of pneumonia, simultaneously with the chill, according to 
Klein ; preceding the exudation, according to Limbeck, and having 
repeatedly been found on the first day of the disease. In one of the 
writer's cases 25,000 cells were counted within four hours after the 
beginning of the first symptom, a sharp chill, while Rieder and Laehr 
found a marked increase within six hours of the chill. Theoretically 
the leucocytosis shoidd be preceded by a period of hypoleucocytosis, 
but this period has never been observed clinically, except in fatal 
cases with prolonged hypoleucocytosis. 

The maximum increase is reached usually just before the crisis 
(Hayem, Klein, Bieganski), but has been observed on the first day 
of the disease or on succeeding days. When the leucocytes increase 
slowly they usually diminish slowly, and the disease defervesces by 
lysis. Peculiar cases of marked severity in which there was no dis- 
tinct leucocytosis until the temperature began to fall are reported by 
Bieganski and Turk. 

During the high febrile movement there is usually little alteration 
in the leucocytosis, but extension of the lesion to other lobes, or to 
adjoining serous membranes, may cause irregular rises in the count. 
Yet in a case in which bronchial breathing passed successively up 
one side of the chest and down the other, the writer found rather 
uniform and high leucocytosis. In six cases Lambert found the 
leucocytes doubled in numbers with the advent of empyema, which 
sometimes failed to raise the temperature or give physical signs. 
Empyema caused a greater increase of leucocytes than did extension 
of the lesion to new lobes, or resolution. 

A few hours before or after crisis the leucocytes begin to diminish 
rapidly, sometimes falling from a high to a normal figure within 
twenty-four hours, after which there are commonly some slight oscilla- 
tions. During lysis the reduction of leucocytes usually keeps pace 
with the temperature, but Limbeck's, Laehr's, and Billings'^ charts 
show some marked upward curves of the leucocytes after lysis. Such 
rises are most often due to complications (Kuhnau^). Several of 
Lambert's cases showed very pronounced increase of leucocytes 
(maximum 100 per cent.) as resolution began. 

In fatal cases there is often a continuous increase (Pick), but some- 
times the leucocytes are high at first, but steadily diminish as the 
patient grows worse (Bieganski, Rieder), while in many fatal cases 
there is no leucocytosis. Hayem believed that in fatal cases without 
leucocytosis the lesion is " less exudative," but subsequent reports 
have shown this view to be inapplicable to the majority of cases. 



PNEUMONIA. 



285 



Alcoholism, virulent infection, and old age are more important 
factors. In four such cases of the writer the lesion was of the 
usual type. In one of these, although the exudate was considerable, 
the marrow of the ribs and vertebrse failed to show the usual hyper- 
plasia. 

Pseudocrises usually have no effect upon the leucocytosis (Limbeck, 
Klein, Laehr, Bieganski), but Turk and others have shown that this 
is not an invariable rule. 

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Temperature. Leucocytosis. 

Course of leucocytosis in pneumonia. (After Laehr.) 



The grade of leucocytosis is usually considerable, and is affected by 
several factors. Hay em found in mild cases 6000 to 12,000 leuco- 
cytes, in moderately severe cases 18,000 to 20,000, and in very severe 
cases a maximum of 36,000. In children the increase is usually 
greater than in adults (Monti, Berggrun, Felsenthal). Severe un- 
complicated cases often show 50,000 cells, while some writers have 
found purulent complications with many of the high leucoeytosos, 
especially when the temperature is relatively low (Smith). The 
highest figures appear to be 115,000, recorded by Laehr, in a peculiar 



286 THE A C UTE INFECTIO US DISEA SES. 

case with delayed resolution. The fever and the leucocjtosis often 
run parallel, but there are numerous individual exceptions to this 
general rule, the most significant of which are the fatal cases, show- 
ing normal or diminished leucocytes. The extent of the exudate has 
considerably more influence upon the leucocytes, as first shown by 
Limbeck. Although contrary conclusions have been reached by 
many writers reviewing short series of cases, it nevertheless remains 
true that the leucocytosis in general bears a rather close relation to 
the extent of the exudate. In the writer's cases, especially in those 
which came to autopsy, this rule was readily verified, although its 
application to individual cases proved unsafe. Thus, in sixty-three 
cases in which one lobe was affected the average number of leuco- 
cytes was 20,000 ; in twenty-four cases with two lobes involved, 
22,700 ; in twelve cases with three lobes, 25,000 ; in one case with 
four lobes, 27,000, and in one in which there was bronchial breath- 
ing over the entire back of chest, 32,000. In ten cases with lesions 
extending to the pleura (empyema), pericardium, and peritoneum the 
average was 17,000 — a tendency toward hypoleucocytosis beginning 
to appear. 

The degree of systemic reaction to the disease chiefly determines the 
grade of leucocytosis. This view, first clearly stated by Rieder, has 
been fully verified by many observers, and embodies the true mean- 
ing of leucocytosis in infectious diseases. In forty-seven cases 
marked by vigorous systemic reaction (temperature 105°, full pulse, 
sthenic condition), the writer found an average of 30,000 leucocytes ; 
in twenty-seven moderate cases (temperature below 105°, symptoms 
less severe), the average was 20,000 ; in twenty-seven cases with 
deficient reaction, 9000, while in twelve asthenic cases the leucocytes 
were subnormal. 

The significance of hypoleucocytosis, observed in many fatal cases, has been 
demonstrated in various experimental infections like those studied by Tschis- 
towitch, who found that rabbits die without leucocytosis when inoculated 
with virulent cultures of the pneumococcus,but with attenuated cultures there 
is leucocytosis and the animals usually recover. 

Types of Leucocytes in Pneumonia. At the height of nearly all 
well-marked leucocytoses in pneumonia the polynuclear neutrophile 
cells form 80 to 95 per cent, of the cells. Turk counted as high as 
96.5 per cent, of these cells, and they are frequently above 90 per 
cent. This high proportion may be seen when the leucocytosis is 
slight or absent, but is usually most marked when the white cells are 
very numerous. At the same time there is a marked reduction, 
relative or often absolute, of lymphocytes to 2 to 4 per cent. The 
large mononuclear cells usually persist in considerable numbers 
(Turk), may sometimes be distinctly increased (Klein), and are 
never entirely absent (Jez). 

The eosinophile cells at the height of the leucocytosis are always 
very scanty and frequently cannot be found after very prolonged 
search (Zappert, Turk). Becker, being unable to find any eosino- 
phile cells in fatal cases, concluded that their complete disappearance 
is an unfavorable sign. 



PNEUMONIA. 



287 



Instead of polynuclear leucocytosis there may be well-marked 
lymphocytosis, as in a case reported by Cabot, in which in a child 
aged six years there were (dQ per cent, of lymphocytes among 94,600 
white cells. Stienon refers to similar cases, and the writer and 
others have observed such inflammatory lymphocytoses in diphtheria. 
Daring defervescence the polynuclear cells diminish rapidly, usually 
to a high normal proportion, at which they are apt to remain several 
days. ^ The lymphocytes at the same time increase in proportion, and 
often in numbers, reaching their normal figures also after a few days. 



Fig. 34. 





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Temperature. Leucocytosis. 

Precritical leucocytosis in pneumonia. (After Limbeck.) 

The large mononuclear leucocytes are usually overabundant at this 
stage, reaching 1 6 per cent, in one of Turk's^ cases, and constituting 
the '^' large-celled lymphocytosis '' described by Klein at this period. 
Eosinophile cells usually reappear in scanty numbers on the day 
before defervescence, or rarely a day earlier (Turk). Distinct post- 
critical eosinophilia occurs in a moderate proportion of cases (Zappert, 
Bieganski), but not in all (Turk). 

In severe cases without leucocytosis the polynuclear cells are 
usually relatively increased (Rieder), but may be normal (Billings), 



288 THE ACUTE INFECTIOUS DISEASES. 

Very often in such cases there is a moderate leucocytosis during or 
after defervescence (Laehr). 

Degenerative Changes in Leucocytes in Pneumonia. Klein described 
numerous " leucocyte shadows" in severe pneumonia. They are 
seen in other infectious diseases, especially diphtheria, and are to be 
classed with the degenerative changes in tissue cells which mark the 
status infectiosus. Glycogen granules in the leucocytes have been 
found in considerable abundance by Livierato and others, usually in 
proportion to the severity of the disease and height of the leucocytosis. 

Myelocytes were found by Turk in nearly all cases. They were 
most abundant about the time of defervescence, and once reached a 
proportion of 11.9 per cent, among 8800 cells. 

Feculiar cells (" reizungsformen '^) of large or small size, with single 
or double nuclei, staining densely and with a brownish tinge by the 
triacid mixture, are described by Turk as of frequent occurrence, and 
as resulting from abnormal stimulation of blood-forming tissues. 

Applications in Diagnosis and Prognosis. The very numerous situa- 
tions in which the examination of the blood is of great value in the 
diagnosis of pneumonia have been pointed out by numerous writers. 
It is especially in such acute uncomplicated infections that the results 
of examination of the blood are to be relied upon, but even here a 
word of warning is needed against too implicit confidence in this or 
any other isolated clinical sign, while it is especially unwise to transfer 
to other fields in blood analysis the rather positive rules which may 
usually be applied to the changes in the leucocytes in pneumonia. 

Barring mild cases, and those fatal ones in which there is no 
increase of white cells, leucocytosis is an invariable accompaniment 
of pneumonia, and its absence is, therefore, very strong negative 
evidence against pneumonia. 

When present, leucocytosis excludes, with somewhat less certainty, 
a considerable class of diseases which are not usually accompanied 
by leucocytosis. These are principally typhoid and typhus fevers, 
malaria, acute tuberculous pneumonia, uncomplicated influenza, and 
the catarrhal pneumonia of influenza (Rieder). 

In prognosis a slight leucocytosis indicates a mild case, while in 
severe cases a low proportion of leucocytes is an extremely unfavor- 
able prognostic sign. This fact was first pointed out by Kikodse and 
V. Jaksch, although such cases had previously been reported by 
Halla and Hayem. Yet absence of leucocytosis appears not to be 
so unfavorable as was at first supposed. Out of fifty-seven severe 
cases without leucocytosis, reported by Halla, Hay em, ^ Laehr, Ewing, 
Sadler, Bieganski, Zappert, Turk, Billings, Cabot, only forty-four 
died, although all of them were unusually severe cases. Lambert 
points out that some severe cases may show absence of leucocytosis 
in the first examination, but later a well-marked increase, whereas a 
continuously low or decreasing number of white cells, as reported in 
three of his patients, is probably seen only in fatal cases. 

The persistence of leucocytosis may be of value in distinguishing 
pseudocrises, but Bieganski, Turk, and others have seen the leuco- 
cytes fall during a pseudocrisis. Continuous or increasing leucocy- 



PLATE XII 



41 



# 



4 



.•5 



4 



^ 



Glycogenic Degeneration of Leucocytes. 
(Iodine and Potassium Iodide in Mucilage of Acacia.) 

Fig. 1. Polynviclear leucoc3^te showing early stage of iodine reaction. 

Fig. 2. Mononuclear and polynuclear cells -^ith circumscribed areas containing glycogen. 

Fig. 3. Pohiiuclear leucocj'te in advanced stage of glycogenic degeneration. From a case of 

purulent peritonitis. 
Fig. 4. Large isolated granules of glycogen in a polynuclear leucocyte. 
Fig. 5. Forms of extracellular glycogen. 



PNEUMONIA. 



289 



tosis after defervescence often indicates a relapse or complication. 
The reappearance of eosinopliile cells indicates that the lesion has 
passed its acme. 

Bacteriology of the Blood in Pneumonia. That infection with 
the pneumococcus may often take the form of a general blood infec- 
tion is indicated by the clinical course of virulent infections in man 
and animals and by the frequent occurrence of the micro-organism 
in the blood of the cadaver. Similar indications are found in the 
report by better and Levy of finding the pneumococcus in the blood 
of a dead fetus whose mother had died of septicemia, and by the 
discovery of the same germ in the milk of a nursing woman who 
was attacked by pneumonia (Bozzolo). 

Numerous bacteriological studies of the blood during life have 
shown also that in a moderate proportion of severe cases the pneu- 
mococcus may be obtained in culture by the usual procedure. 

Sittmann obtained the largest proportion of positive results, 4 out of 16 cases 
examined, three of which were fatal and gave signs during life of general sep- 
ticemia. Similar cases of pneumococcus septicemia are reported by Belfanti, 
Netter, Marchiafava and Bignami, Goldscheider, Grawitz, Bacciochi, and 
others, and it has become evident that in this group of infections the pneu- 
mococcus is usually to be found in the blood during life. Other successful re- 
sults were obtained only a few hours before death from pneumonia, and the pres- 
ence of the pneumococcus in the blood in these cases must be regarded as an 
ante-mortem invasion (Boulay). 

As regards the bacteriological condition of the blood in ordinary 
uncomplicated lobar pneumonia evidence has steadily increased which 
indicates that this disease is often a form of bacteremia, but the 
question cannot yet be regarded as settled. Most of the early 
observers were unable to isolate the pneumococcus from the circu- 
lating blood in any considerable proportion of cases. The following 
table represents the more important work in this field : 

Bacteriological Studies of Blood in Pneumonia. 











Year. 


No. of 
cases. 


Positive results. 


Negative results. 


Author. 


Total. 


Fatal. 


Total. 


Fatal. 


Sittmann .... 




1894 


16 


4 


3 


12 


3 


Kraus, Kuhnau . 








1897 


21 


2 


2 


19 




Kohn . 








1897 


32 


9 


7 


23 




James, Tuttle . 








1898 


12 





12 


10 


Sello . . . 








1898 


48 


12 


10 


27 


9 


White . 








1899 


19 


16 


16 


3 





Beco . 








1899 


49 


7 


5 


42 


15 


Silvestrini, Sertoli 








1900 


16 


15 




1 




Prochaska . 








1900 


50 


50 


12 







Pieraccini . 








1900 


28 


11 




17 




Landi, Cionini . 








1900 


27 


25 




o 




Cole . 








1902 


30 


9 9 


21 


4 



19 



290 THE ACUTE INFECTIOUS DISEASES. 

Prochaska's results Avere remarkable, as he claims to have found 
the pneumococcus in all of a series of fifty cases, twelve fatal. He 
sowed 10 c.c. of blood in distinctly alkaline broth. Sometimes, 
especially in cases with metastatic inflammations, staphylococcus 
aureus or streptococcus were found associated with the pneumococcus. 
Some of his examinations occurred as early as the second day. He 
naturally claims that bacteremia is invariable in the disease, but 
he found no relation between the leucocytosis and the grade of bac- 
teremia and no relation to prognosis. 

It appears premature to draw positive conclusions from these 
varying results. Fraenkel claims to have verified Prochaska's con- 
clusions, but Cole, who sowed more blood than Prochaska, secured 
rather few positive cultures. None of the recent observers mention 
the difficulty of distinguishing the pneumococcus from the strepto- 
coccus. 

From these studies it may be concluded that when pneumonia 
leads to metastatic inflammations the pneumococcus is frequently 
found in the blood ; that in some cases the blood is invaded just 
before death ; and that in uncomplicated pneumonia the pneumo- 
coccus is rarely found in the blood during the progress of the lesion^ 
and that when it is present the disease is usually fatal. 

DIPHTHERIA. 

Red Cells. The concentration of the blood demonstrated to a slight 
degree in pneumonia is even more distinct in the highly febrile stages 
of diphtheria. Grawitz refers the tendency to a lymphogogic action 
of diphtheria toxin which he has observed clinically and experi- 
mentally to cause an increase in the specific gravity of the blood. 
Although Bouchut found an average of 4,300,000 cells in ninety- 
three cases, a distinct reduction, yet many of his observations were 
made late in the disease, and individual cases often showed slight 
polycythemia. Cuffer reported extreme polycythemia, 7,200,000 to 
7,800,000 in three cases. Later observers, especially Morse and 
Billings, have closely followed the changes in the red cells, finding 
high normal proportions, 5,100,000 to 5,600,000 during the first 
week. In the second week Morse found even higher numbers, once 
6,800,000, while Billings, although finding an average loss of 500,000 
cells, encountered some cases with distinct polycythemia. With 
the fall in temperature slight anemia appears in many cases, but 
not in all. Bouchut and Billings observed losses of 2,000,000 cells 
in several cases. 

Morphological changes in the red cells are not marked, but when 
anemia develops there is slight polychromasia and the usual deficiency 
of Hb. Nucleated red cells were noted by Engel. The Hb is 
slightly diminished in the average case, but may be considerably 
reduced in cases which have lost many red cells. Billings found an 
average loss of 10 per cent, in patients not receiving antitoxin. 

The Leucocytes. The early observers, Bouchut, Cuffer, Pee, 
Halla, Limbeck, and Pieder, fully established the presence of leuco- 



DIPHTHERIA. 291 

c\i:osis in diphtheria, but only Bouchut attempted to deduce any 
rules governing its occurrence. He observed an increase in all cases, 
usually proportionate to the severity of the disease, but in septicemic 
cases the increase was less marked and the prognosis fatal. In view 
of the recent observations of many myelocytes or an extreme propor- 
tion of lymphocytes in diphtheria, Bouchut's statement that the blood 
of diphtheria may be " leukemic ^^ is not far from the truth. More 
detailed studies were contributed later by Gabritschewsky, Morse, 
Ewing,^ Billings,^ Engel, Schlesinger, and File. 

The leucocytosis of diphtheria resembles in most respects that of 
pneumonia. It begins very early when the disease develops sud- 
denly, and reaches its highest point within one or two days, or begins 
more slowly and increases steadily for several days or until death. 
It probably begins earlier and reaches its acme sooner in more refrac- 
tory individuals, with whom the prognosis is comparatively good. 

The writer observed two cases without leucocytosis until the fourth 
and sixth days. In one of these the condition was probably refera- 
ble to prolonged toxic hypoleucocytosis, and the patient died later. 
Xot infrequently the white cells begin to rise only after deferves- 
cence, while long persistent leucocytosis is also of rather common 
occurrence. In favorable cases the leucocytes usually diminish 
steadily after the first few days. In fatal cases the leucocytes may 
steadily increase or may steadily decrease during the days before the 
fatal issue, or there may be no leucocytosis. 

The height of the leucocsrbosis is usually considerable, 25,000 to 
30,000 cells being frequently present in severe cases. The majority 
of fatal cases at some period show between 25,000 to 50,000 cells, 
hence the conclusion of Gabritschewsky that a high and progressive 
leucocytosis is a bad prognostic sign. Mild attacks, especially in 
adults, may not show any increase. The writer found 72,000 cells 
in one case with lymphocytosis, while in a peculiar case marked 
by hemorrhagic eruption Felsenthal counted 148,000 — possibly an 
agonal hyperleucocytosis. The grade of leucocytosis is little affected 
by the fever, but in many cases is proportional to the extent and 
depth of the membrane. It may be distinctly affected by pneumonia, 
but the writer failed to find any uniform lymphocytosis when the 
cervical nodes were greatly enlarged, nor did the character of the 
infection, whether pure or mixed, appear to influence the leucocytes 
(cf. File). In general, the leucocytosis of diphtheria is less marked 
than that of pneumonia with equal temperature, and less than that 
of non-diphtheritic angina of equal extent (File). 

Types of Leucocytes in Diphtheria. With well-marked leucocytosis 
the polynuclear neutrophile cells are usually much increased in num- 
bers and proportions, but they very seldom reach the very high ratios 
seen in pneumonia, probably on account of the greater tendency of chil- 
dren to lymphocytosis. Lymphocytes, probably for the same reason, 
are relatively more abundant. A striking lymphocytosis occurred 
at the height of the disease in two of the writer's cases, in one of 
which the lymphocytes, large and small, formed GO per cent, of 
72,000 leucocytes, and in another 62 per cent, of 22,500 cells. In 



292 THE ACUTE INFECTIOUS DISEASES. 

neither was there marked enlargement of cervical lymph nodes. Of 
quite different significance is the relative lymphocytosis without 
increase in total numbers which may be seen in the earlier stages of 
the disease, and was noted by Billings in a fatal case without leuco- 
cytosis, and by Rieder and File during convalescence. Eosinophile 
cells are usually reduced in proportions, often persist in low normal 
ratio, and frequently cannot be found at all. They are relatively 
more numerous than in pneumonia. 

Engel made the interesting observation that myelocytes, both 
neutrophile and eosinophile, are frequently present in the blood of 
diphtheria, and that when these cells form over 2 per cent, the prog- 
nosis is very unfavorable. In cases which recovered the myelocytes 
never formed over 1.5 per cent., while in seven fatal cases they ran 
from 3.6 per cent, to 14.6 per cent. It should be added that the 
numbers of myelocytes varied greatly from day to day, and that 
eight of thirty-two patients died with few or no myelocytes in the 
blood. 

Degenerative changes in the leucocytes in diphtheria are often well 
marked. The ' ' leucocyte shadows " of Klein are seen in all severe 
infections and may become very numerous in fatal septic cases. 
Even before the cells become fragmented many of them, principally 
the poly nuclear forms, show deficiency of chromatin and of neutro- 
phile granules. The writer, examining the blood in 0.6 per cent, 
salt solution tinged with gentian violet, found a striking deficiency 
of chromatin in a case in which the leucocytosis disappeared before 
death. In the other septic and fatal cases also it was plainly appar- 
ent, although not demonstrable in less severe infections. This change 
in the leucocytes, which may be seen in other infectious diseases, and 
especially in acute leukemia, must be classed with the general cellular 
degenerations which mark the status infediosus. Its significance in 
diphtheria has been fully discussed by Gabritschewsky, v/hile File 
believes that these pale-staining cells are necrotic. The writer 
believes that, with careful technique, variations in the staining 
capacity of leucocytes may be made of value in prognosis. 

An increased acidophile tendency of the neutrophile granules 
appeared to be demonstrable in some of the writer's fatal cases. 
Kanthack has also noted a similar change in the staining tendency 
of the pseudoeosinophile granules in rabbits which had received 
small injections of microbic poisons. 

Effects of Antitoxin upon the Blood in Diphtheria. The red 
cells show no distinct or uniform effects from the injections of anti- 
toxin, although in some healthy subjects there is a moderate reduc- 
tion lasting a few hours. On the other hand, the use of antitoxin, 
by limiting the progress of the infection, tends to prevent further 
destruction of blood cells. 

Within half an hour after the injection of antitoxin, the leucocytes, 
especially the polynuclear forms, if previously abundant, show a 
marked diminution, and in most cases, although the leucocytosis 
returns after twenty-four to forty-eight hours, it seldom reaches its 
previous grade. 



DIPHTHERIA, 293 

The writer noted the redaction of leucocytes after antitoxin in all 
but two fatal cases, while Schlesinger found it in all of his exami- 
nations. It has also been noted by File. In the writer's cases the 
loss was from 4000 to 15,000, but Schlesinger observed a loss of 
20,000 within seven hours after the injection. In some fatal cases 
the use of antitoxin is followed immediately by distinct hyperleuco- 
cytosis (the writer, Gundobin). The most favorable cases show 
a steady diminution of w^iite cells after the injection, but in many 
fatal cases this reduction is interrupted after the third or fourth day. 
In critical cases with many pale-staining leucocytes the writer found 
an improvement in the staining quality of many polynuclear cells 
shortly after the injection of antitoxin. In some fatal cases this 
change could not be detected. 



CHAPTEE XII. 

THE EXANTHEMATA. 
VARIOLA. 

Red Cells. During the febrile period Hayem found very little 
change in the red cells, while in the stage of suppuration polvcy- 
themia was sometimes to be noted. Immediately after defervescence, 
when the destruction of blood cells through the septic process was 
no longer masked by the concentrating influence of fever, the red 
cells showed a sudden reduction. In a case of confluent smallpox 
there was a loss of 2,000,000 cells. In a fatal case before death 
there were 4,600,000 cells, while in another, markedlv hemorrhagic, 
there were only 2,000,000. 

Pick, from his study of forty-two cases, fonnd very little change 
in the red cells throughout the entire course of the disease. He 
failed to find any severe anemia, although many of his cases were 
hemorrhagic and confluent. In severe cases which recovered the red 
cells remained normal before the eruption, almost invariably increased 
during the suppurative stage, even in hemorrhagic cases, and after 
defervescence or before death were rarely found much below their 
original figure. 

The usual condition of the blood after smallpox appears to be, 
therefore, a mild form of chlorotic anemia, while under some rather 
unusual conditions this anemia may become severe. 

Leucocytes. Although leucocytosis was demonstrated in the 
eruptive stage of variola by Brouardel, Hayem, Halla, and Pee, the 
detailed knowledge of the subject has been contributed principally 
in the studies of Pick, and of Courmont and Montagard. 

]\Eild cases of varioloid with scanty eruption ran their course, under 
Pick's observation, with normal or subnormal numbers of leucocytes, 
but when suppuration occurred the leucocytes were increased, reach- 
ing in one case 20,000. 

In nearly all of Pick's cases of variola there was distinct leucocy- 
tosis beginning with the appearance of vesicles, increasing as the 
exudate became purulent, and reaching its height when suppuration 
became most active. 

In cases which recovered the leucocytes returned slowly to the 
normal as suppuration subsided. Abscesses frequently interrupted 
recovery and caused marked exacerbations of the leucocytosis. In 
seven of eight cases dying of pneumonia there was a rapid and steady 
decrease of leucocytes, although suppuration continued. The grade 
of leucocytosis was usually proportionate to the severity of the septic 
process. 



THE EXANTHEMATA. 295 

Failing to find leiicocytosis in the high febrile periods of the early 
stages of severe cases, Pick concluded that variola uncomplicated does 
not tend to produce leucocytosis, but that the usual leucocytosis is 
referable to secondary infection. This conclusion must be doubted. 

Courmont and Montagard have also contributed an extensive study 
of the blood of variola, and their results require a modification in 
some respects of the conclusions of Pick. They observed a mixed 
leucocytosis with excess of lymphocytes in nearly all cases, beginning 
in the early stages of the eruption, reaching its acme in the pustular 
stage, and in uncomplicated cases slowly declining. In uncompli- 
cated cases the leucocytosis was usually slight, and varied between 
10,000 to 20,000, but once reached 33,000 before the development 
of any pustules. In confluent and fatal cases there were usually 
more than 20,000 leucocytes. In hemorrhagic cases the leucocytosis 
was usually more marked, and in two cases reached 39,000 and 
41,000 on the fourth day, the day of death. In some fatal cases the 
leucocytes tended to diminish markedly toward the end of the dis- 
ease, from 19,700 on the ninth day to 2500 four hours before death. 
In subjects who had never been vaccinated the leucocytosis was 
distinctly greater than in vaccinated subjects. 

The increase affected principally the lymphocytes, the polynuclear 
cells, with few exceptions, being below normal in percentage, though 
usually increased in actual numbers. 

They properly distinguish between pustulation and true secondary 
suppurative complications, such as boils and abscesses. The former 
condition did not increase the percentage of polynuclear cells, 
although the pustules constantly yielded streptococci in cultures. 
Boils and abscesses, however, usually ran the percentage of poly- 
nuclear cells above normal. They conclude from these observations 
that pustulation is not the result of secondary infection of the skin, 
but is a part of the true variolous process. 

In a detailed study of the varieties of leucocytes occurring in 
variola, it appears that the majority of new cells are medium- sized 
lymphocytes which constitute usually 35 to 45 per cent, of the white 
cells. The authors attribute great importance to the presence of 5 
to 10 per cent, of very large mononuclear non-granular leucocytes in 
the blood of variola. Neutrophile myelocytes were never absent, 
occurring in an average of 3 per cent, of all cells, Avith extremes of 
2 to 16 per cent. Marked eosinophilia was observed in one hemor- 
rhagic case which recovered under serum therapy. On the second 
day in a fatal case 15,000 white cells were counted, of which 3 per 
cent, were mast-cells. A few nucleated red cells were always to be 
found, except in infants, most numerously in hemorrhagic cases. As 
the diagnostic features of the blood in variola, much reliance was 
placed upon the presence of lymphocytosis with excess of very 
large cells and associated with neutrophile myelocytes in moderate 
proportion. 

Very similar results were obtained bv Weil, who found slight 
leucocytosis, 6000 to 10,000, in six cases; 6000 to 15,000 in thir- 
teen cases; 15,000 to 20,000 in nine; 20,000 to 25,000 in throe ; 



296 THE ACUTE INFECTIOUS DISEASES. 

25,000 to 30,000 in three ; 30,000 to 35,000 in one ; above 35,000 in 
one. The leucocytosis was most marked at the period of yesicola- 
tion, while with pustnlation the leucocytes increased or diminished 
or remained stationary. In cases which were fatal without complica- 
tions there was usually a diminution of leucocytes before death. The 
increase of large mononuclear cells and myelocytes was characteri.><tic, 
especially in cases ending in streptococcus septicemia. In the pus- 
tules he found 10 to 20 per cent, of mononuclear cells and myelo- 
cytes, and 30 to 60 per cent, of polynuclear cells. While claiming 
that the pustulation is not due to secondary infection he found that 
the pustules always contain streptococci, which make their appear- 
ance very suddenly, as on one day he would find none and on the next 
enormous numbers. 

The writer examined the blood in twelve cases of variola at 
various stages. Distinct leucocytosis was found in only six of the 
cases, but the low proportion of polynuclear cells was always observed 
if complications were absent, and once at the height of pustulation 
only 21 per cent, of these cells were present. A few myelocytes, 
however, were seen in only five of the cases. It was found, as did 
Courmont and Montagard, that the low proportion of polynuclear 
cells exists in the blood when the cutaneous lesions contain pus and 
streptococci. 

Until the contagium of variola is discovered and until the relation 
of the streptococcus to the disease is determined it will probably 
remain undecided whether the leucocytosis of the disease is referable 
to the true virus or to the streptococcus. It is certain that leuco- 
cytosis is absent in the very early stages in many cases of ordinary 
severity, but it is also true that the streptococcus is often multiply- 
ing in the cutaneous lesions before any pronounced leucocytosis 
appears in the blood, and when the peculiar increase of mononuclear 
cells is prominent. 

In the marrow of variola Roger, Josue, and Weil found very little 
reaction in adult cases, corresponding to slight leucocytosis observed 
clinically. In children with bronchopneumonia leucocytosis was 
marked and the hyperplasia of the marrow was distinct. In the 
adult marrow they found an excess of mononuclear cells and diminu- 
tion of polynuclears. 

Biological Examinations of the Blood in Variola. In 1887 G. PfeitFer 
called attention to the presence in vaccine lymph of small unicellular ameboid 
bodies, and the following year he found these same bodies in human lymph. 
These observations were soon confirmed by Rieck, and later by Ogata, who 
classed the bodies as protozoa, order gregarinidce. 

Guarnieri, in 1892, believed that he had cultivated the same bodies in the 
epithelial cells of the rabbit's cornea, and although Ferroni and Massari claimed 
that Guarnieri's parasites were degenerating nuclear products, some but not all 
subsequent observers have succeeded in verifying Guarnieri's conclusions. 

In 1894 Pfeiffer reported the discovery of amebse in the blood of smallpox 
patients, describing them as free in the plasma, about one-fourth the size of 
red cells, possessing one or more nuclei, and projecting pseudopodia. 

Weber and Doehle have described in the blood of measles, scarlet fever, and 
smallpox, several forms of ameboid bodies which they believe to be develop- 
mental stages of a parasitic protozoon. 



THE EXANTHEMATA. 297 

In 1897 Eeed found pigmented ameboid bodies in the blood of vaccinated 
monkeys and children, and in the blood of variola, but he found the same 
bodies in normal subjects, and he could not demonstrate any nucleus. 

Kruse, reviewing the evidence in 1897, ascribed great significance to Guar- 
nieri's bodies in the epithelial cells of the cornea, believing that they represent 
the first stage in the solution of the etiology of variola, but he did not grant 
equal importance to the bodies found in the blood. 

Widal and Bezancon are reported to have found streptococci in the blood of 
six cases of variola, and Arnaud in two primary hemorrhagic cases. The 
writer^ sowed in broth 10 c.c. of blood in five cases of variola of ordinary 
severity and found all the cultures sterile. Only one of the cases died. 

Serum therapy in variola has been attempted by Courmont and 
Montagard by the use of calf seram drawn fifteen days after vaccina- 
tion. The treatment seemed to lessen complications, while the 
injections usually caused a diminution of the leucocytes in cases 
showing leucocytosis. 

VACCINIA. 

Billings, in fourteen infants, noted a moderate but distinct poly- 
nuclear leucocytosis, usually about 15,000, maximum 20,000. 

Sobotka examined the blood of forty-three children after vaccina- 
tion, making the following observations : 

The red cells and Hb showed no constant variations, and usually 
remained normal. 

Vaccination always caused a leucocytosis, beginning usually on 
the third or fourth day after inoculation and gradually falling until 
the seventh or eighth day, when the leucocytes were frequently sub- 
normal. From the tenth or twelfth day a secondary leucocytosis 
regularly appeared, lasting two to six days, and showing close rela- 
tion to the activity of the virus and the number of the pustules. 

The height of the first leucocytosis varied between 12,000 and 
23,000; that of the second between 10,000 and 17,500, while in 
the intermediate period the cells fell as low as 3500. In uncompli- 
cated cases the lowest figures usually corresponded to the highest 
temperature, the leucocytosis preceding by several days the local and 
general manifestations of vaccinia. 

Similar changes are noted in infants by Enriquez and Sicard, but 
they failed to detect the intermediate decline observed by Sobotka. 
In these cases the mononuclear cells numbered 60 to 70 per cent., 
the polynuclear 30 to 40 per cent., and once there were 3 per cent, 
of myelocytes. Of twelve cases in adults they found leucocytosis, 
10,000 to 12,000, in only four. In seven rabbits vaccination, which 
proved fatal in two to three weeks, caused well-marked large-celled 
lymphocytosis. 

VARICELLA. 

Engel^ found 67 per cent, of polynuclear cells, with absence of 
eosinophiles, in a child at the height of the pustular stage. Three 
days later, when most of the pustules were healed, the polynuclear 
cells had fallen to 47 per cent., and the eosinophiles risen to 1 6 per 



298 THE ACUTE INFECTIOUS DISEASES. 

cent. The total numbers of leucocytes were not stated, but the above 
proportions indicate a moderate leucocytosis. 

Nobecourt and Merklen, in fifteen cases, found no change in the 
red cells and little in the leucocytes. In seven cases there was an 
excess of large mononuclear cells, in six slight polynuclear leucocy- 
tosis, maximum 4500. The eosinophiles were nearly always dimin- 
ished. In five cases there were 1 to 12.5 per cent, of myelocytes. Weil 
and Descos, from a study of twenty cases, concluded that varicella 
sometimes yields a slight polynuclear leucocytosis, maximum 13,500, 
while in thirteen of their cases the leucocytes were within normal 
limits. They state that the absence of large mononuclear cells and 
myelocytes will serve to distinguish varicella from variola. Stengel 
and White, in four cases, found distinct leucocytosis but once, and 
in a patient suffering from bronchitis. 

From these somewhat discrepant results it will be seen that the 
blood in varicella may not differ in any particular from that of mild 
cases of variola. 

SCARLET FEVER. 

Hayem gave the first systematic account of the blood changes in 
scarlatina, finding a loss of about 1,000,000 red cells after deferves- 
cence, and a moderate leucocytosis in average cases, much increased 
by severe angina or by suppurative processes. Somewhat isolated 
observations were reported by many of the earlier blood analysts, 
Halla, Pee, Pick, Reinert, Sadler, while considerable series of cases 
were studied by Rieder and Kotschetkoff. 

The whole blood suffers in a slight degree the usual effects of fever. 
The formation of fibrin is usually increased, especially when there 
are extensive angina or suppurative complications (Hayem). Heubner 
noted hemoglobinemia in one case, representing the septicemic type 
of the disease. 

Red Cells. The gradual loss of red cells noted by Hayem was 
fully verified by Kotschetkoff, who found a reduction to 3,000,000 
or lower in nearly all cases. The regeneration of the blood was slow 
and complete only after six weeks or longer. On the other hand, 
Zappert found less than 4,000,000 cells in only one of six cases, and 
very slight anemia was noted in a considerable number of cases 
examined at varying periods by Leichenstern, Arnheim, Pee, Pick, 
Peiner, Sadler, Felsenthal, and Vandenberg. When complications 
supervene, however, as nephritis or endocarditis, very severe anemia 
may rapidly develop. In such cases Yandenberg reports as low as 
25 per cent, of Hb, 2,000,000 red cells, and specific gravity 1031. 
In the late stages of fatal cases this severe anemia may be referred 
to the widespread occurrence of the streptococcus. 

Leucocytes. Kotschetkoff classified the leucocytoses in three 
groups, the mild cases, showing between 10,000 and 20,000 white cells, 
the moderately severe cases, with 20,000 to 30,000 cells, and very severe 
and usually fatal cases with a leucocytosis of 30,000 to 40,000 cells, 
while in some rapidly fatal cases over 40,000 leucocytes were found. 
Yet Rieder's ten observations never gave more than 25,000 cells, 



THE EX A N THE MA TA. 299 

and usually less than 20,000, although some of his cases were com- 
plicated with pneumonia and croupous pharyngitis, and were fatal. 
FelsenthaPs six cases in children were of moderate severity and 
showed 18,000 to 30,000 cells. 

The leucocytosis begins one to two days before the appearance of 
the rash, reaches its height with or shortly after the full development 
of the eruption, and while in some cases rapidly falling with the erup- 
tion, usually continues for four to five days longer, and very often 
persists for days or weeks after the temperature has become normal. 
Mackie, who found leucocytosis in twenty-five cases, places the 
period of greatest leucocytosis in mild cases at the fourth day after 
the appearance of the rash. 

The grade of leucocytosis seems in general to correspond wdth the 
severity of the disease, especially of the angina, but not with the 
height of the temperature. Complications such as lymphadenitis, 
otitis, nephritis, usually have little effect on the leucocytes (Kotschet- 
koff), but Pee observed two cases in which the leucocytosis increased 
when the lymph nodes began to swell late in the disease. Pneumonia 
caused but slight increase in some of Eieder's cases. Mackie counted 
95,300 cells in a case of septic angina, and noted a steady decrease 
of white cells in a fatal case. 

Types of Leucocytes. The percentage of polynuclear cells is in all 
cases much increased, varying from 85 to 98 per cent., according to 
the intensity of the disease, reaching the highest point on the second 
day of the exanthem, and thereafter slowly declining. In fatal cases 
the proportion of polynuclear cells falls but slightly, or soon regains 
or passes the original figure. 

The eosinophile cells may shoio characteristic variations. In all but 
very severe cases they are normal or subnormal at first, steadily 
increase after two to three days, reaching a maximum of 8 to 15 per 
cent, in the second or third weeks, and thereafter, declining slowly, 
reach the normal figure about the sixth week. In ten cases Reckzeh 
found that they began to increase on the first day, reached an average 
of about 6 per cent, on the seventh to eighth days, thereafter gradually 
diminishing until the fourteenth day. In fatal cases they may 
disappear early in the disease. The lymphocytes are at first dimin- 
ished, but later rise to normal proportions. 

The above rules deduced by Kotschetkoff, while probably repre- 
senting the average case, are not always applicable. Thus Weiss 
found no eosinophiles in one case at the height of the exanthem. Rille 
observed marked eosinophilia in a fatal case ; Bensaude observed as 
high as 20 per cent, of eosinophiles in one instance ; Klein reports 
lymphocytosis during convalescence; and many writers (Rieder, 
Turk) have described a high persistent leucocytosis, especially in 
those cases followed by nephritis or other complications. Turk 
has called attention to the remarkable change which the leucocytes 
undergo about the fifth day of the disease, when the polynuclear 
cells rapidly diminish and eosinophiles and lymphocytes rapidly 
increase, 
similar phenomenon seen in variola. 



300 THE ACUTE INFECTIO US DISEASES. 

Bacteriology. Although the specific contagium of scarlet fever 
has not been demonstrated, practically all observers who have dealt 
with the cadavers of such cases have found a coccus widely distributed 
in the viscera and blood. Many have found in this coccus certain 
characters which they believe could distinguish their particular micro- 
organisms from streptoGocous pyogenes, while others, dealing appar- 
ently with the same germ, have been content to class it with the 
polymorphous streptococcus. Very few of these observers have 
attempted to demonstrate the presence of the germ in the blood dur- 
ing life, nearly all reports being concerned with its occurrence in the 
blood after death. Charlton, however, claims to have isolated a 
streptococcus from the circulating blood of all those cases, in a series 
of twenty-five, in which the examination was made during the first 
five days of the disease. 

Baginsky and Sommerfeld have collected about all the available 
evidence which indicates that the only micro-organism constantly 
present is the streptococcus pyogenes, and that this germ is the specific 
contagium. 

Kurth, d'Espine and Marignac, and Class, Gradwohl, and Page, 
have endeavored to maintain an independent position for certain 
cocci which they succeeded in isolating from the throat, skin, and 
cadaver, occasionally from the circulating blood. 

Raskin found streptococcus pyogenes in the circulating blood in two 
of sixty-four cases, while all other cultures were sterile. Negative 
results were obtained in two cases by Sittmann and in four cases by 
Kraus. 

At present it is impossible to decide what is the relation between 
the different cocci described, what is their relation to the disease, or 
how frequently they are to be found in the circulating blood. 

MEASLES. 

The red cells have been found in the great majority of cases to 
suffer little or no change, but a loss of Hb is usually demonstrable 
after defervescence. Reckzeh mentions the occurrence, in very 
severe cases, of anemia with unusual variations in the size of the cells, 
with microcytes, macrocytes, and normoblasts. 

In adults uncomplicated measles seldom causes leucocytosis, but is 
characterized rather by hypoleucocytosis, reaching in one of Rieder^s 
cases 2700 cells. From 4000 to 6000 cells are commonly seen. 
This fact was first noted by Pee, and has been confirmed by Pick, 
Rieder, Rille, Felsenthal, and others. 

Considerable variations in the behavior of the leucocytes in the 
first days of measles are apparent in the numerous reports collected 
by Reckzeh. 

Normal or slightly reduced numbers of white cells are usually 
present at the onset of the disease. Combe finds that the decrease 
begins during the last two days of the period of invasion and becomes 
more marked during the stage of eruption. Sobotka and Cazal, 
however, observed hyperleucocytosis before the eruption appeared. 



THE EXANTHEMATA. 301 

At the height of the exanthem they are usually at their lowest figure 
(Pee, Turk), and return to the normal within a few days or a week 
after defervescence. When the bronchitis is severe there may be a 
moderate leucocytosis, Hayem finding 10,000 to 14,000 cells in such 
cases occurring in children. Rieder observed slight leucocytosis in 
a case complicated by catarrhal pneumonia. Cabot observed 9000 
cells in two cases, one hemorrhagic. The writer found no leucocy- 
tosis in three cases occurring in malarious subjects. The malarial 
parasites reappeared, with chills, during convalescence. 

The proportions of the various leucocytes show no distinctly 
abnormal changes. Turk found a rather high percentage of poly- 
nuclear cells during the fever, with diminution of small lymphocytes, 
and Reckzeh's tables also show a high proportion of polynuclear 
cells, 62 to 88 per cent., on the third and fourth days. Pee, Klein, 
Turk, and Combe noted an excess of large mononuclear cells appear- 
ing with the eruption. The eosinophiles are usually in low normal 
proportions during the early febrile period, and tend to diminish as 
the eruption declines. Yet Turk found nearly 6 per cent, during the 
second week of the disease. 

Bacteriological examination of the blood was negative in ten cases 
examined by Barbier. Weber claims to have found in the blood of 
measles a protozoon, which he has also seen in variola. 

Applications in Diagnosis. Typical cases of measles and scarlet 
fever may sometimes be distinguished from each other in their early 
stages by the examination of the blood. Yet, as Turk says, the blood 
in measles strongly resembles that of a mild scarlatina, as both show a 
nearly normal number of leucocytes and normal proportions of 
eosinophiles. Yet equally severe constitutional disturbaace should 
give, on the second to third days, leucocytosis, if scarlatinal ; normal 
or diminished leucocytes, if from measles. 

In German measles there was no leucocytosis in two cases men- 
tioned by Cabot. 



CHAPTEE XIII. 

TYPHOID FEVER. 

The whole blood commonly suffers concentration in the early 
stages of the disease as a result of the febrile process^ while at any 
period profuse diarrhea and repeated hemorrhages considerably 
reduce the total bulk. This concentration is so marked and constant 
that the deep-red appearance of the blood drop in typhoid fever is a 
very characteristic differential sign between this disease and perni- 
cious malaria. 

Fibrin formation is usually deficient and may not be demonstrable 
at all, but with inflammatory complications this element may reap- 
pear and become abundant (Hay em, Turk). 

Red Cells. During the febrile period the red cells usually show 
a slight and gradual decline. Yet the initial concentration of the 
blood often yields moderate polycythemia during the first two weeks 
or longer, so that the slight anemia is not to be noticed until the 
fever and diarrhea subside (Sadler, Felsenthal). Many observers 
have found over 5,000,000 red cells in individual cases at varying 
periods of the fever, while Thayer reports nearly 7,000,000 in the 
first, second, and third weeks. At such times a considerable grade 
of pre-existing anemia may be obscured by the febrile concentration 
of the blood. Even when distinct polycythemia does not result the 
same factors tend to keep up the proportion of red cells, so that in 
the vast majority of cases of typhoid fever the red cells number more 
than 4,000,000, and in order to demonstrate an anemia referable to 
the disease it is necessary to follow the case from the first. That the 
typhoid toxemia tends nevertheless to produce anemia is clearly 
shown in the large series of cases reported by Thayer and Da Costa^ 
in which there is each week a progressive loss of red cells and Hb, 
the weekly loss averaging for the first five weeks 100,000 to 500,000 
red cells and 5 to 6 per cent, of Hb. 

The Hb suffers to a great extent, and in spite of the concentration 
of the blood most febrile cases register between 60 and 80 per cent, of 
Hb. Severe diarrhea or large hemorrhages may at any time cause 
marked oscillations in the red cells and Hb. After and often before 
defervescence the blood may show distinct anemia, which, with rapid 
defervescence, may appear suddenly (Arnheim, Zaslein, Boeckman^ 
Laache). During convalescence the anemia slowly disappears, the 
Hb being restored much later than the red cells. 

The grade of anemia observed after typhoid fever varies greatly 
with the character of the disease. Uncomplicated cases may show 
no distinct reduction of cells and very slight loss of Hb. In a con- 
siderable proportion of severe cases the red cells fall below 4,000,000 



TYPHOID FEVER. 303 

and the Hb below 70 per cent. Kohler, in twenty-nine cases, found 
an average loss of 19.4 per cent, of Hb in men and 20.4 per cent, in 
women, while the average of red cells for men was 4,030,000 and for 
women 3,580,000. Thaver's average for the fourth week was 
4,200,000 and Da Costa^s 3,500,000. Hayem, Thayer, Henry, and 
others have reported severe grades of pernicious anemia as sequelae of 
typhoid fever. In one of Henry's cases there were only 804,000 
red cells. 

Morphological changes are usually not marked, but in severe cases 
Turk found megalocytes, small microcytes, and polychromasia in 
comparative abundance. Nucleated red cells may appear after 
hemorrhage. 

Leucocytes. Numbers. In the first week uncomplicated cases 
nearly always show a normal number of leucocytes, but severe angina,, 
bronchitis, enteritis, etc., may yield a moderate polynuclear leucocy- 
tosis. Klein and Aporti regarded this initial leucocytosis as of fre- 
quent occurrence, but most other observers have failed to encounter 
it. The Avriter has seen so many examples of moderate polynuclear 
leucocytosis in the first week of typhoid fever that he would warn 
the observer that the behavior of the leucocytes at this time is quite 
variable, and that complications can seldom be discovered to account 
for the leucocytosis. 

In the second week the leucocytes usually show a distinct reduc- 
tion, especially of the polynuclear forms, but the number of leuco- 
cytes found at this time is by no means constant. 

In some cases the lowest figures of the disease are reached in the 
second week (Turk, Chetagurow), while in others there is no distinct 
reduction at this time (v. Jaksch,'-^ Sadler). 

In the third and fourth weeks the leucocytes usually continue ta 
diminish until the acme of the disease is reached (Turk), after which 
they slowly increase. In many cases the lowest figures are reached 
at this period (Rieder, Turk, Thayer), but sometimes the reduction 
continues until after defervescence (Klein). 

The average course of leucocytosis is shown in Thayer's collection 
of 826 examinations : 

Examinations. Leucocytes. 

First week 119 6442 

Second " 258 6251 

Third " 200 5528 

Fourth " 117 5431 

Fifth " 70 5510 

sixth •' 25 5690 ' 

Seventh " . 14 6132 

Eighth " 14 6614 

Ninth " 7 5057 

Tenth " 2 5000 

A relation between the leucocytes and the fever seldom exists, nor 
does the size of the spleen appear to influence the number or type 
of the leucocytes (Turk). That the reduction of the white cells is 
dependent on the action of the typhoid toxin is indicated by the 
further losses which commonly go with unfavorable turns in the dis- 



304 THE ACUTE INFECTIOUS DISEASES. 

ease (Rieder, Jez, Turk, Nagaeli). It is therefore a general rule that 
the more severe the typhoid intoxication the lower is the count of leuco- 
cytes. The reduction is seldom below 2000 cells, but 1000 to 2000 
were reported by Hay em, Limbeck and Eieder, Cabot, and Koliler. 
The majority of cases at some periods show between 4000 and 6000 
cells, and many fall below 4000. 

Leucocytosis during the later course of typhoid fever is by no 
means uncommon. Da Costa claims that it is present at some period 
in about 10 per cent, of all cases. Usually a severe diarrhea from 
extensive ulcers, or hemorrhage, or pneumonia, or other exudative or 
suppurative complications, may be found to explain the increase. 
Yet several reported cases with leucocytosis have shown no such 
complications (Aporti), and a short experience at the bedside seldom 
fails to bring to light some moderate leucocytoses without apparent 
cause. Courmont and Barbaroux observed polynuclear leucocytosis 
(89 per cent.) throughout an uncomplicated fatal relapse, and in 
several cases at some time during the continuous pyrexia, usually at 
its acme, there was an increase of polynuclear cells. In grave cases 
they frequently found a series of elevations of the polynuclear cells, 
and conclude that the typical course of the leucocytes can be expected 
only in cases of moderate severity. On the other hand, leucocytosis 
may fail in the presence of pneumonia or other markedly exudative 
complications (Turk, the writer, Cabot). Kohler found 6200 and 
4200 leucocytes in cases complicated by severe bronchitis. After 
hemorrhage in one case the white cells remained at 2600 ; in two 
others there was an increase of about 4000 cells. In eleven cases of 
hemorrhage Thayer observed a reduction of red cells, and after 
twenty-four hours a leucocytosis, maximum 24,800, in only half the 
cases. 

Complicating pneumonia once reduced the leucocytes from 2600 
to 1000 ; at another time they remained at 6300, and twice 1 1,200 
and 11,800 cells were counted (Kohler). 

Regarding the effects of the numerous other inflammatory compli- 
cations of the disease it appears that the occurrence or failure of 
leucocytosis is quite as uncertain as after pneumonia. 

Cold baths have long been known to cause temporary massing of 
leucocytes in peripheral capillaries (Winternitz). In twenty cases 
Thayer^ found an average increase of 5346 cells, and a maximum 
increase of 17,000. With the return of peripheral circulation the 
excess of cells disappears. 

Perforation usually causes polynuclear leucocytosis, but there may 
be no effect upon the leucocytes, or the percentage of polynuclear 
cells may rise without increase in their total number. 

One may refer the failure of leucocytosis after perforation to the 
low condition of the patient or to the discharge into the peritoneum 
of much septic material, or to violent infection by the streptococcus, 
as in three cases reported by Thayer. As Russell found, leucocy- 
tosis in these cases may be due not so much to the perforation as to 
the subsequent peritonitis, and may, therefore, be delayed until after 
other signs have become urgent. The leucocytosis when present 



TYPHOID FEVEB. 305 

may be very evanescent, and its presence may in general be regarded 
as more favorable than its absence. 

Types of Leucocytes. Daring the first week of the disease the 
persistence of a normal proportion of lymphocytes without noticeable 
increase of neutrophile cells is a very characteristic feature of typhoid 
blood. Barring the occasional occurrence of initial polynuclear 
leucocytosis, from the end of the first week there is a progressive 
increase of the lymphocytes and diminution of the neutrophile cells. 
At first the lymphocytes do not pass beyond high normal limits, but 
during the third, fourth, and fifth weeks, or later, they usually occur 
in distinct excess. While mononuclear cells seldom fall below 25 
per cent, at any stage of the disease, a proportion of 40 to 60 per 
cent, is often seen. Among these cells the proportion of small 
lymphocytes is often striking, but usually the medium-sized leuco- 
cytes are most abundant. In some cases there is a very marked 
absolute lymphocytosis. In one of the writer's cases at Montauk 
the blood resembled that of lymphatic leukemia, a resemblance 
rendered still more striking by the enormous size of the mesenteric 
nodes at autopsy. AVith the increase of mononuclear cells the num- 
bers of polynuclear cells gradually fall, reaching 60 to 65 per cent, 
in most cases and occasionally a much lower figure (35 per cent., 
Jez ; 20 per cent., Klein). The excess of lymphocytes usually per- 
sists during the first weeks of convalescence, and may not reach its 
acme until this time, while Ouskow found that normal relations were 
not restored until the tenth or eleventh week. Nagaeli describes 
the development during convalescence, especially in children, of a 
well-marked lymphocj^tosis with a moderate increase of neutrophile 
cells. In children this lymphocytosis was most marked two or three 
months after the fever, while in adults it was less marked and dis- 
appeared by the end of the second month. 

Eosinophile cells are usually absent or very scarce during the 
febrile period, but reappear shortly before (JSTagaeli), during, or 
after defervescence. Aporti found as high as 18 per cent, during 
the intermittent pyrexia at the end of the disease, but they are 
usually much less abundant. 

Degenerative changes in the leucocytes occur as usual, Jez reporting 
large numbers of pale leucocyte shadows in severe cases. Glycogen 
was found in the leucocytes in increased quantity between the twelfth 
and twentieth days by Livierato. 

Applications in Diagnosis. The morphological examination of the 
blood is often of great assistance in the diagnosis of typhoid fever and 
the diseases which simulate it. The writer knows of no clearer 
illustrations of this fact than those which he reported^ in 1893, and 
which have been paralleled from numerous later observations and 
by many writers both before and since. 

Suppurative processes, if active, may usually, but not always, be 
distinguished from typhoid fever by the presence of polynuclear 
leucocytosis. Yet it should be remembered that slow suppuration, 
or the mere presence of pus the secretion of which has ceased, are 
frequently unaccompanied by leucocytosis or are even marked by 

20 



306 THE ACUTE IXEECTIOUS DISEASES. 

relative lymphocytosis. Thus the writer found 50 per cent, of 
lymphocytes among 11,000 cells in a case of large abscess of the 
liver with mild typhoidal symptoms, and 45 per cent, of lymphocytes 
among 7000 cells with the chest full of pus. With increasing 
experience, therefore, the writer believes that most careful observers 
will recognize the partial justice of Grawitz's claim that in difficult 
cases the blood examination here often fails to be of service. 

Among the conditions which, by the almost invariable presence of 
leucocytosis, may be distinguished from typhoid fever, are bacterial 
endocarditis, suppurative appendicitis, and pneumonia. Malaria of 
sufficient gravity to simulate typhoid fever can nearly always be 
distinguished by the anemic appearance of the blood drop as com- 
pared with the deep red, concentrated blood of typhoid fever. An 
astonishing change in the blood was often noted at Montauk when 
typhoid fever developed in subjects of malarial cachexia, and in no 
instance were malarial parasites found in such concentrated blood. 
In acute paroxysms the discovery of the parasite is usually possible, 
but chronic malaria without parasites in the blood may simulate 
typhoid fever. 

Between miliary tuberculosis, typhoid fever, and some forms of 
meningitis, AVidal's test is required and the enumeration of leuco- 
cytes is of little value. 

From an extensive study of the leucocytes in typhoid fever Nagaeli 
draws the following conclusions regarding prognosis. The prognosis 
is favorable: (1) When eosinophiles are present at the height of the 
disease, or reappear in the second or third stages of the febrile 
period. (2) AVhen lymphocytes begin to increase after the severest 
toxemia is past. (3) The diminution of neutrophile cells is slight 
only in more favorable cases. Unfavorable signs are : (1) Very small 
numbers of all varieties of leucocytes. (2) Failure of leucocytosis 
with complications. 

Bacteriological. In the hope of developing a method of early 
diagnosis of typhoid fever many biological studies of the blood have 
been undertaken. Aspiration of the spleen has given successful results 
in the majority of cases (Chantemesse and AYidal, Redtenbacher, 
Lucatello, Xeisser, Bruschettini), but this dangerous procedure cannot 
be generally adopted. The results of Silvestrini,who found the typhoid 
bacillus in the aspirated blood of the spleen in four cases in which 
there were no characteristic intestinal lesions, are most suggestive. 

In blood drawn from the rose spots, while early attempts were rather 
unsuccessful, Xeuhaus and later observers have been able to isolate 
the typhoid bacillus in nearly all cases often before the appearance 
of AYidal's reaction. Scholz and Krause recommend that the test be 
made as soon as possible after the spots appear, since they found that 
the bacillus disappeared after three to five days. 

Richardson plants the material curetted from five or six incised 
spots, as well as the blood which oozes from the incisions. Freezing 
by ethyl chloride diminishes the pain of the operation. 

Bacteriological studies of blood in typhoid fever usually gave nega- 
tive results until Kuhnau reported eleven positive cultures in forty- 



TYPHOID FEVER. 307 

one cases, examining blood drawn from the basilic vein at the acme 
of the disease. 

In 1900 Auerbach and Unger pointed out that large dilutions in 
broth are necessary to annul the bactericidal action of the blood, and 
they secured positive results in seven of ten cases by planting ten to 
thirty drops in 300 c.c. of broth. The growth was at first often 
scanty and the bacilli non-motile and thread-like, but grew abun- 
dantly in subcultures. Later it was shown that the bacillus is very 
constantly present in the blood in early stages of the disease, but 
may disappear in the third w^eek or with defervescence. Thus, 
Schotmuller was successful in forty of fifty cases ; Castellani, in 
twelve of fourteen cases; Cole, in eleven of fifteen, and Hewlett, in 
twenty of twenty-four ; while Courmont,^ who was successful in nine 
consecutive cases, claims that the bacillus can always be isolated 
from the blood before the decline of the disease, although more than 
one culture may be required. 

Not only have these recent studies demonstrated that typhoid fever 
is probably always a form of bacteremia, but it has been shown that 
the characters of the bacterial strains concerned in typhoid fever 
vary considerably, each producing highly specific agglutinins in the 
blood (Achard and Bensaude, Widal, Gwyn, Gushing, Schotmuller, 
Kurth, and Buxton). 

That the disease may assume the character of a mixed septicemia 
is indicated by a considerable number of reports of the presence in 
the blood of other bacteria, especially staphylococcus aureus (Loison, 
Sittmann, Kraus, Pennato). 

Serum Therapy in Typhoid Fever. For a history of this sub- 
ject and a consideration of its problems and the various attempts that 
have been made to meet them, the reader is referred to the author's 
review,* which includes literature up to 1902. 

The most noteworthy results in serum treatment of typhoid fever 
are those of Chantemesse. This investigator began in 1896 to inject 
horses with very toxic cultures of bacillus typhosus, secured and 
handled anaerobically. In 1901 he treated 100 cases with the serum 
thus obtained which had very high agglutinative properties and 
strong preventive powers in animals. The mortality was 6 per cent., 
the chief value of the treatment proving to be in the relief of 
symptoms and in shortening the course of the disease. Three of the 
fatal cases died of perforation, against which the treatment was of 
little avail. Two of the fatal cases were critically ill of pneumonia 
when treatment was begun. The serum caused rapid defervescence 
and improvement in all symptoms. Occasioually the temperature 
rose again after ten days of improvement, but the relapse, though 
often severe, was promptly controlled by the serum. The injections 
caused distinct leucocytosis for twenty-four to forty-eight hours, 
after which the neutrophile cells diminished and eosiuophile colls 
reappeared. 



308 THE ACUTE INFECTIOUS DISEASES. 

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TYPHOID FEVER. 309 

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310 THE ACUTE INFECTIOUS DISEASES. 

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CHAPTER XIV. 

WIDAL'S TEST. 

The history of the development of WidaPs test from the discovery 
of the phenomenon of Pfeiffer in 1894 through its first application 
to the diagnosis of typhoid fever by Pfeiffer and Kolle, and Gruber 
and Durham, in 1896^ up to its more practical modification by 
"^Yidal, has now been very fully reviewed in numerous monographs 
and treatises on bacteriology and need not here be repeated. It may 
only be said that while the scientific basis of the test had been firmly 
laid by previous studies, up to the time of Widal's communication 
there had been no indication that the specific reaction could be 
obtained from small quantities of serum and at the beginning of the 
disease, while the use of dried blood and the introduction of the test 
into municipal laboratories, thus rendered possible, was first accom- 
plished by Johnston, of Montreal. 

Description of the Reaction. When to a few cubic centimetres 
of blood serum of a patient suffering from typhoid fever is added a 
few drops of an actively motile culture of bacillus typhosus, the bac- 
teria are precipitated in flakes, leaving the supernatant fluid clear. 
\yhen the sediment is examined microscopically it is found that the 
bacilli have lost their motility and are agglutinated in masses, while 
with very intense reactions they may be broken up into granules or 
even completely dissolved. When the test is performed with a drop 
of dissolved blood inoculated by means of a platinum loop with a 
small portion of broth culture, all stages of the reaction may be fol- 
lowed under the microscope. 

With very intense reactions the agglutination is found to be com- 
plete as soon as a cover-glass can be adjusted over the drop and the 
specimen placed under focus. The bacilli are motionless, they are 
nearly all gathered in characteristic clumps, which stretch in a net- 
work irregularly through the field, and very soon, in some cases, 
evidences of subdivision or solution of the bacteria may be detected. 

If the reaction is less complete, the clumps are less compact and a 
few motile bacilli may be found betv/een the masses. With high 
dilutions of the blood, all stages of the reaction may be followed. 
The first change noted is a partial loss of motility. The bacilli cling 
to one another after struggling to free themselves, but gradually 
entangling their neighbors. In the course of ten or fifteen minutes 
the process results in the gradual clumping of all bacilli, or, accord- 
ing to the strength of the reaction, a variable number of actively 
motile bacilli may remain between the loose masses. 

When the reaction /,s' present in traces only, much longer time is 
required for the appearance of small clumps, but those reactions 



312 THE ACUTE INFECTIOUS DISEASES. 

must be discarded as unreliable. All experienced observers have 
insisted that distinct islands of clumped bacilli must be present to 
constitute a positive reaction, and Fischer and others maintain that 
all bacilli must be rendered quiescent before the result can be regarded 
as positive. 

Wilson describes as a partial reaction one in which well-defined 
clumps appear in every field, but composed of motile bacilli, while 
the edges of the hanging drop are not free from bacilli. He found 
such reactions in thirteen different diseases. 

Pseudoreactions. While partial reactions occur under many 
conditions when the technique has been faultless, certain effects 
simulating the true agglutination may appear in specimens contain- 
ing not a trace of the specific principle on which the test depends. 
In old cultures many loose clumps of bacteria may be transferred by 
the loop from the culture tube and be mistaken for an effect pro- 
duced by the serum. Normal blood or serum, in somewhat concen- 
trated form, exerts a marked influence upon the motile typhoid 
bacillus, causing it to lose its motility after a time, but failing to 
develop typical clumps. If the specimen has been allowed to dry 
many bacteria adhere to slide or cover-glass or gather at the thicken- 
ing edges of the specimen, and sometimes these collect in motionless 
groups. Such clumps always lack the reticular arrangement seen 
in the true reactions. A considerable variety of confusing appear- 
ances will meet the beginner, resulting from the formation of fibrin 
and the incomplete solution of masses of 7'ed cells. 

Technique : Methods of Obtaining the Body Fluid. Although 
specific reactions have been obtained from many secretions, excre- 
tions, and other fluids of the body, only the blood, its serum 
expressed from the clot, or the fluid gathering in blisters, yield 
sufficiently constant results to be available in clinical diagnosis. 

The Whole Blood. When the examiner can reach the bedside 
there is no better method than to employ the whole blood diluted in 
known proportion by distilled water. In order to obtain an accurate 
dilution a medicine dropper may be graduated in one and ten or 
twenty drop marks, as suggested by Cabot, but such dilution cannot 
be very accurate. The writer has long used for this purpose the 
leucocyte pipette of the Thoma-Zeiss hematocytometer, which gives 
an exact dilution of 1 : 20 or 1 : 50, or more, and which is itself 
a very convenient instrument for handling the blood. Levy and 
many others have devised special tubes adapted to this purpose. 
The chief objection to this method is the failure of the blood to com- 
pletely dissolve in dilution of 1 : 20 or 1 : 50 of w^ater, but no other 
method can furnish more exact dilution, which is essential in accurate 
work. This difficulty may be avoided by laying the pipette on the 
side until the corpuscles settle. 

Blood dried on a glass slide and dissolved by mixing with water 
is now used in probably 90 per cent, of all examinations. One or two 
drops are touched to a clean glass slide and dried in the air. Such a 
specimen protected from moisture may be kept for days, transported 
for long distances, and being easily obtained, even by the patient 



WIDAL'S TEST. ' 31 a 

himself, furnishes by far the most practical method of obtaining the 
necessary material for the test. Its great disadvantage is the impossi- 
bility of securing an exact dilution of the blood when it is redissolved. 
This difficulty, while theoretically insurmountable, proves to be of 
comparatively little moment in practice, since an experienced worker 
can learn to control the dilution by the color of the drop. Also, 
when imperfectly dissolved the detritus of red cells may obscure the 
field, although it should not fail to be distinguished from masses 
of bacilli 

Some observers have found less powerful and constant effects 
from dried blood than from serum (Widal, Delepine, Johnston), but 
for diagnostic purposes Park finds the two methods of nearly equal 
value. Nevertheless, for accurate studies of variations in the reac- 
tion, the use of dried blood is inapplicable, although it will probably 
always remain in extensive employment for simple diagnostic pur- 
poses. 

Serum. 1. The Bulbed Tube. A capillary tube with central 
bulb is filled by capillary attraction from the expressed drop, the 
ends are fused, and when the blood coagulates a few drops of serum 
are exuded. A great many modifications suited to individual pur- 
poses have been suggested for this method. It offers considerable 
technical difficulties, but furnishes serum without delay. 

2. The Blister. Serum may be obtained by means of a Spanish 
fly blister in from six to eighteen hours, and in quantity sufficient 
for extended examination without involving much pain or incon- 
venience. The fluid may be drawn in a sterile test tube and after- 
ward divided in measured quantities, or it may be sealed in a capil- 
lary tube. For detailed study blister serum is superior to all other 
fluids. For measuring serum the ^^ mixer ^' of the hematocytometer 
is well adapted, and the test may be performed in the hanging drop 
or in the test tube. 

The Culture. Considerable difference in the response of different 
cultures of bacilli have been demonstrated by Kolle, Achard and 
Bensaude, Durham, v. de Velde, and Ziemke. Although Foerster 
found very little difference in a considerable series of cultures, most 
observers agree that attenuated cultures are more readily agglutinated. 
Miiller succeeded in greatly diminishing the agglutinability of a 
given species and at the same time increasing its virulence by passing 
it through animals. It appears that for each culture there is a limit 
beyond which normal serum is positively inert, while at the same 
dilution typhoid serum exerts a specific action (Foerster). AVhile 
any pure culture may be used, Miiller and others have shown that a 
freshly isolated culture is not suitable for diagnostic use, and must 
first be transplanted many times in artificial media. The best results 
have been obtained in New York City by a so-called " Pfeift'er 
specimen " imported by Park. k. stock culture of this particular 
growth is kept in sealed tubes of nutrient agar in the ice chest and 
replanted every few months. From this growth the specimen 
employed in testing is obtained in broth culture grown for twenty- 
four hours at a temperature of 37° C. In such broth cultures tlie 



314 THE ACUTE INFECTIOUS DISEASES. 

bacilli are completely isolated and actively motile, so that the slightest 
change in motility or tendency to clump can be detected by com- 
parison with a control specimen. 

Dead Bacilli. Widal first observed that cultures of typhosus 
which had been killed by heat (57° to 60° C, thirty to forty-five 
minutes) had lost little or none of their capacity to agglutinate, and 
this fact has been abundantly attested by others. Many have there- 
fore preferred to use a dead culture killed by heat, or by 10 per 
cent, formalin, or by thymol, or by corrosive sublimate, 1000 to 5000 
(Park), thereby dispensing with the trouble of preparing a fresh 
culture. Such an expedient, however, can hardly meet with general 
adoption, on account of the difficulty of keeping the dead bacilli well 
isolated, and because the gradual loss of motility is a desirable and 
reassuring feature of the test in mild reactions, which are just the ones 
in which uncertain clinical signs render a positive test more desirable. 

Attenuated cultures have been recommended by Johnston, who 
found that in using dried blood pseudoreactions were not infre- 
quent with active virulent cultures, while broth cultures planted 
from old agar stock were less susceptible and did not respond to 
healthy or non-typhoid sera. 

Paratyphoid Strains. From the observations of Achard and 
Bensaude, Widal, Gwyn, Gushing, Schotmuller, Kurth, Coleman 
and Buxton, and others, it has been shown that the bacteria in 
typhoid fever may show certain characters, such as the fermentation 
of sugars with the production of gas and acid, which gives them an 
intermediate position between typhosus and bacillus coli communis. 
Buxton has shown that these intermediate forms, isolated by him- 
self and obtained from the above observers, may be still further 
classified into three rather distinct groups. It appears, also, that the 
agglutinins developed by these strains are highly specific, that of one 
group usually having little effect on other groups. Buxton found 
a certain grade of interaction between the members of his groups. 
These considerations suggest that where the blood is negative to 
typhosus it should be tested with various paratyphoid strains. The 
writer attempted to do this in a short series of cases of suspected 
typhoid fever, but where the reaction was negative to typhosus it was 
negative also to the paratyphoid cultures. 

Degree of Dilution of Serum and Time Required. Although it has 
been believed that the serum reaction in typhoid fever depends on 
the presence in the blood of a peculiar substance which exerts a 
specific action on the typhoid bacillus, yet it has been found that in 
a considerable proportion of cases healthy serum, or that of patients 
suffering from other diseases, contains substances which exert a very 
similar influence upon typhoid cultures. In typhoid fever , however, 
the serum may usually be diluted twenty to fifty times, or often very 
much further (1000 to 2000, WidaF) without destroying the reaction, 
while in other diseases the reactions usually disappear with dilutions of 
1 : 10, or almost certainly with dilutions of 1 :20. 

' The element of time is also of great importance in distinguishing 
the specific typhoid reaction from that produced by other sera. 



WIDArS TEST. 315 

While a distinct reaction often occurs instantly with typhoid sernm^ 
blood of other diseases almost never acts immediately, bnt requires 
one-half to one hour or longer to disclose its effects. 

Consequently, in order to demonstrate the specific typhoid reaction, 
it is necessary to increase the dilution and to limit the time. 

'' The results obtained in the New York City Health Department 
laboratories and elsewhere have shown that in a certain proportion of 
cases of typhoid there occurs a delayed moderate reaction in a 1 : 10 
dilution of serum or blood ; but very rarely, if ever, excepting in 
typhoid fever, does a complete reaction with this dilution occur within 
five minutes. When dried blood is used the slight tendency of non- 
typhoid blood in 1 : 10 dilution to produce agglutination is increased 
by the presence of fibrinous clumps and perhaps by other substances 
derived from disintegrating red cells. From many cases examined 
by Fraenkel, Stein, Foerster, Scholz, ourselves, and others, it has 
been found that in dilution of 1 : 20 or more, a decided quick reaction 
is never produced by any febrile disease other than typhoid infection, in 
which it often occurs in dilution of 1 : 50^^ (Park). 

Yet even this dilution appears insufficient to eliminate all sources 
of error, and there has been a constant tendency among experienced 
workers to increase the grade of dilution. Grunbaum placed it at 
1 : 30 ; Simon, at 1 : 30 or more ; Stern, after a large experience, at 
1 : 40 ; and Mewius, at 1 : 60. 

From these authoritative opinions it becomes necessary to prescribe 
a dilution of at least 1 : 20, better 1 : 30, while the limit of time 
should not be greatly extended. Even these limits will be found 
insufficient to avoid all possible error, and in doubtful cases one 
should use a dilution of 1 : 40 or 1 : 60, increase the time to one 
or two hours, and require a distinct result. 

Occurrence of the Reaction. Statistics vary considerably 
regarding the dates of occurrence and the constancy of the reaction 
in typhoid fever. 

Cabot collected over 3000 cases of supposed typhoid fever, of 
which 95 per cent, gave the reaction at some period of their course, 
while in 2500 control cases, not typhoid, 2 per cent, gave positive 
reactions. 

Park reports positive results in a large series : 

During the first week, in 20 per cent, of the cases. 

" second " 60 " " " 

third " 80 " 

fourth " 90 " 

" second month, in 75 " 

In 88 per cent, of hospital cases in which repeated examinations 
oould be made, a definite reaction was obtained at some period of the 
disease. 

Wilson reports further on the work of the New York City Department of 
Health, as follows : In 256 examinations the test was positive in 8 cases not 
diagnosed as typhoid, while 3 were malaria, and I puerperal sepsis with tuber- 
culous intestinal ulcers. Of 1115 cases 117 which gave no reaction proved to 
be typhoid. 



316 THE A C UTE INFECTIO US DISEASES. 

The earliest date of appearance ol Q. positive reaction has not been 
and cannot well be determined in the human subject, but in animals 
inoculated with dead typhoid bacilli the reaction appears between the 
third and eighth days. In man a positive reaction has been found 
by Johnston and Taggart, and by Fraenkel, on the second day, but 
the reactions were not sharp. Levy found the first distinct reac- 
tion on the sixth day in the human subject inoculated with dead 
typhoid bacilli. It may be found before the appearance of rose 
spots, splenic tumor, or the diazo reaction in the urine. During the 
course of the disease the reaction may continue without interruption, 
or may be absent one day while present the next. It may be absent 
entirely in mild cases, may appear only in a relapse (Lichtheim,. 
Breuer, Thoinet), may disappear entirely after a few days (Elsberg), 
or may persist for months or even a year. Incomplete reactions 
have been reported after many years (Stewart). It not infrequently 
appears for the first time during convalescence or may exhibit a 
sudden increase at this time. According to Widal, in the majority 
of cases the reaction disappears by the fifteenth to thirtieth day of 
convalescence, but Stewart believes that it persists at least one year 
in 50 per cent, of the cases, for two years in 25 per cent., and for ten 
years in 5 per cent. His conclusions can only apply to very indis- 
tinct reactions. 

In the blood of the fetus delivered during the course of typhoid 
fever, several observers have failed to find any agglutinative power 
(Mahnt, Stahelin), but Schumacher^ claims that agglutinins are always 
present in the fetus during the last month of pregnancy, but that 
their persistence is of short duration. 

Relation of the Reaction to Other Features of the Disease. 
In some cases the reaction is most intense at the height of the dis- 
ease, as in cases observed by Jemma. Widal and Sicard, who 
found that in the active stage a dilution of 1 : 60 or 1 : 80 does not 
usually prevent the reaction, noted a marked weakening as convales- 
cence proceeded, some cases failing to react with dilution of 1 : 10. 
They noted a reaction in one case with a dilution of 1000 or 12,000. 
Foerster, who found a reaction in dilutions varying from 1 : 60, 
1000, or 5000, could not detect any relation between the intensity of 
the reaction and the severity of the disease. Pfeiffer and Kolle, and 
Foerster have shown that the agglutinating power has no relation to 
the bactericidal activity of the serum. 

Courmont^ has contributed an elaborate study of the course of the 
agglutinative power of the blood in typhoid fever, reaching some 
important conclusions regarding prognosis and offering evidence that 
the agglutinative power of the blood is closely connected with the 
defensive reaction of the organism. His conclusions are as follows : 

In the great majority of cases of typhoid fever of ordinary or 
moderate severity the power of agglutination reaches a maximum at 
the period of defervescence, or during the first days of apyrexia, and 
falls, often rapidly, with the fever, or during convalescence. Agglu- 
tination curves that are continuously low (less than 1 : 200) are 
rarely seen in cases of moderate severity, but frequently in very 



WIDAL'S TEST, 317 

toxic forms of the disease which are prolonged or fatal. Very irreg- 
ular agglutination curves with premature fall are rare in moderate 
cases, very frequent in toxic and fatal cases. In some prolonged cases 
the curve of agglutination rises rapidly shortly before defervescence. 
In relapsing cases the agglutination curve varies, but usually fol- 
lows the same types as in single attacks. It is usually higher in the 
relapse than in the initial attack if the patient recovers and lower if 
he dies. In mild and irregular types of the disease the power of 
agglutination is very variable and usually low or evanescent. 

Effect of Typhoid Serum upon the Colon Bacillus. Although 
Fraenkel in a large series of cases reported that typhoid serum has 
no marked power to agglutinate the colon bacillus, and recommended 
the use of this serum in the separation of colon from typhoid bacilli, 
this claim has not been verified. Stern and Biberstein found, very 
shortly, five cases of typhoid fever of which the blood serum agglu- 
tinated the colon bacillus even more powerfully than the typhoid, 
and many other observers, including Park, Rodet, Courmont, 
Ustvedt, Bensaude, and Kuhnau, have had similar experiences in 
many cases. Baumgarten, therefore, concludes that this method can 
no longer be accepted as yielding positive proof of the identity of 
bacillus Goli communis. It nevertheless remains true that a bacillus 
which on cultural characters falls between the typhoid and colon 
groups, is almost certainly coli communis, if it is not agglutinated by 
a well-tested and active typhoid serum. The possibility that infec- 
tion by the colon bacillus is intermingled with that of bacillus 
typhosus in enteric fever has been abundantly considered by several 
writers. The safest method of identifying the colon bacillus is not by 
the serum of a case of typhoid fever, but by the serum of an animal 
which has been inoculated with a pure culture of bacillus typhosus. 

Reactions in Conditions Other than Typhoid Fever. In view 
of the fact that positive reactions have been obtained both with 
healthy serum and in diseases other than typhoid fever when a 
dilution of 1 : 10 was used, many observers have recommended that 
higher dilutions only be employed. Thus Schultz obtained com- 
plete reactions in eleven of 100 cases of various febrile diseases with 
a dilution of 1 : 10 ; in seven cases with a dilution of 1:15, and in 
three with 1 : 20, while a faint response followed a dilution of 1 : 25 
in a single instance. The time limit, however, was one to two hours. 
In single cases complete reactions with dilutions of 1 : 10 or more 
have now been reported in so many cases that it is no longer possible 
to refer the resul^ts to faulty technique. 

Some of these conditions are as follows : septicemia (Ferrand) ; 
malaria (Bloch, Villiers, Catrin, and the writer) ; pneumonia (Kasel 
and Mann) ; tuberculosis (Wesbrook, Jez, d^Espine) : otitis (Stern) ; 
influenza (Wesbrook) ; typhus (Park) ; meningitis (v. Oordt) ; nor- 
mal serum (Kuhnau). 

In many of these cases the dilutions were from 1 : 10 to 1 : oO, or 
more, and the clumping was prompt and complete. 

In several cases of chlorosis Kohler claims to have secured a reac- 
tion in a dilution of 1 : 40, and in a case of severe anemia at 1 : nO. 



318 THE ACUTE INFECTIOUS DISEASES. 

A large percentage of cases of jaundice have been found to show 
high aggkitinative power over bacillus typhosus, which Greenbaum 
refers to the presence of taurocholic acid. 

In Weil's disease Eckhart obtained positive reactions in two cases, 
and Zupnik, in four of six cases of WeiFs disease, two of cholelith- 
iasis, one of cholangitis, and one of carcinoma of the liver, all the 
subjects being jaundiced. 

Stewart, using dry blood in 538 cases, found typhoid lesions at 
autopsy in five which failed at three periods during the disease to 
give a positive reaction. Thompson also reports six. negative results 
in 163 cases, while a slight reaction was obtained in 12 per cent, of 
various conditions other than typhoid fever. Ustvedt encountered a 
peculiar epidemic of typhoid fever among soldiers in which four of 
fifteen cases failed to yield a reaction. Total failure of reaction, 
under full precautions, is also reported in single cases by Artaud, 
Haushalter, Schumacher, Fischer, and others. 

The significance of these negative results have been made apparent 
by the work of various observers, who have shown that a consider- 
able number of bacterial strains, each developing highly specific 
agglutinins, may give rise to the symptoms of typhoid fever. 

Value in Diagnosis. The difficulty in determining the value of 
Widaks test in diagnosis arises principally from the divergent opin- 
ions regarding the essential features of a complete reaction. Although 
the belief in the specific quality of WidaFs reaction has been aban- 
doned, the test remains an extremely valuable diagnostic procedure 
under several conditions. 

It must be granted at once that absolute certainty cannot be 
ascribed to any test unless the dilution has been very high, certainly 
not less than 1 : 60, with a time limit of not more than fifteen to 
thirty minutes. 

A positive result with much less dilution (1 : 30) must stand as 
almost certain evidence that the disease is typhoid fever. Such results 
are usually obtainable, however, only after the disease is well estab- 
lished and its clinical symptoms distinct. Accordingly the chief 
value of the test lies in its capacity to distinguish, during the height 
of the illness, certain conditions, such as acute gastritis, tuberculosis, 
meningitis, and pneumonia, which may simulate typhoid fever. 

The application of the test in the early diagnosis of typhoid fever 
has, in the experience of most observers, proved disappointing. It 
is rarely to be found until other signs render the diagnosis very prob- 
able, when the blood test may often be added, as any other isolated 
clinical symptom, to the evidence for or against typhoid fever. 

The Avriter believes, however, that the combination of an indistinct 
serum reaction, diminution of fibrin, absence of leucocytosis, and 
presence of relative or absohite lymphocytosis, can very rarely be 
demonstrated in the early stages of any obscure febrile disease except 
typhoid fever. The morphological examination of the blood is, 
therefore, a valuable adjunct and control in the application of WidaFs 
test, and the writer believes that in doubtful cases it should never 
be omitted. 



WIBAL'S TEST. 319 

Negative results are of very moderate import until the third or 
fourth week, and unless often repeated, while some reported cases, 
often fatal, have failed at any time to yield the reaction. In case of 
a negative result in a case strongly resembling typhoid fever, one 
should if possible test the blood with various paratyphoid strains. 

Summary. The most reliable method for clinical purposes is the 
use of fresh blood diluted with water in a graduated pipette, and 
inoculated as a hanging drop preparation. Blood or blister serum 
should be employed for more extended study, while the use of dried 
blood, sometimes necessary, gives very slightly less reliable results. 

The culture should be grown in broth at 37° C, twenty-four hours 
old, actively motile, and of moderate virulence. A recognized brand 
should be obtained if possible, and the behavior of all newly isolated 
cultures should be tested before use, and replanted until they become 
readily agglutinable. 

A positive reaction consists in the complete immobilization of all 
bacilli and the compact clumping of the great majority. 

A time limit of five minutes is all that is necessary, with dilutions 
of 1 : 20, in the great majority of positive reactions. With higher 
dilution (1 : 40) the time may be extended to thirty minutes, and 
with dilution of 1 : 60, to two hours (Mewius). 

A dilution of at least 1 : 20 is required in all positive reactions, 
with which, however, occasional errors will occur. Dilutions of 
1 : 30 or 1 : 60 are to be strongly recommended, for the higher the 
dilution the more certain are all positive results. 

A negative result is of little import unless obtained during the 
height of the disease (third to fifth weeks) and on repeated examina- 
tions. In the great majority of cases the reaction disappears within 
a few weeks after convalescence, and several authentic cases, usually 
fatal, have not given a positive reaction at any time. 

The agglutinative power of typhoid serum is usually slight and 
transient in mild cases, marked and persistent in cases of average 
severity, low or variable in toxic cases, but bears no constant rela- 
tion to the gravity of the disease, and gives no certain prognostic 
indications. 

Bibliography. 

WiDAL 's Test. 

Achard, Bensaude. Compt. Rend. Soc. Biol., 1896, p. 940. 
Artaud. Presse Med., 1898, No. IS, p. 106. 
Bensaude. L 'Agglutination des Microbes, Paris, 1897. 
Biberstein. Zeit. f. Hj^giene, Bd. 27, p. 347. 
Biggs, Park. Amer, Jour. Med. Sci., vol. cxiii. p. 274. 
Block. Jour. Amer. Med. Assoc, 1897, vol. xxix. p. 7. 
Breuer. Berl. klin. Woch., 1896, p. 1037. 
Catrin. Soc. des Hop., 1896, p. 698. 

Courmont. Compt. Rend. Soc. Biol., 1898, p. 756. Also, Sert^-proiiiiosiic d. 1. 
fiev. typh., Paris, 1897. 

Delepine. Brit. Med. Jour., 1897, I., p. 1894. 

Durham. Lancet, 1896, II., p. 174(). 

Eckhart. Mimch. med. Woch., 1892. Xci. 27. 

Elsbcrg. N. Y. Med. Record, vol. li. p. 510. 

d'Espine. Rev. med. de la Suisse Uomande, 1S9S, p. 113. 



320 THE A C UTE INFECTIO US DISEASES. 

Ferrand. BuU. Soc. d. Hop , 1897, p. 104. 

Fischer. Zeit. f. Hygiene, Bd. 32, p. 407. 

Foerster. Zeit. f. Hygiene, Bd. 24, p. 500. 

Fraenkel. Miinch. med. Woch., 1897, p. 107. 

Gruber, Durham. Miinch. med. Woch., 1896, pp. 206, 285. 

Grunhaum. Brit. Med. Jour., 1897, II., p. 1852. 

Haushalter. Presse Med., 1896, p. 505. 

Jemma. Cent. f. inn. Med., 1897, p. 65. 

Jez. Wien. med. Woch., 1897, p. 98; 1898, p. 890. 

Johnston. N. Y. Med. Jour., 1896, vol. Ixiv. p. 573. 

Johnston, Taggart. Brit. Med. Jour., 1896, II., p. 1629. 

Kohler. Cent. f. Bact., Bd. 29, p. 683. 

Kolle. Deut. med. Woch., 1897, p. 132. 

Kasel, Mann. Miinch. med. Woch., 1899, p. 581. 

Kuhnau. Berl. klin. Woch., 1897, p. 397. 

Levy. Miinch. med. Woch., 1897, p. 1435. 

Lichtheim. Cited by Foerster. 

Mahnt Cent. f. Bact., Bd. 30, p. 675. 

Mewius. Zeit. f. Hygiene, Bd. 32, p. 422. 

Muller. Miinch. med. Woch., 1903, p. 56. 

V. Oordt. Miinch. med. Woch., 1897, p. 327. 

Pfeiffer. Zeit. f. Hygiene, Bd. 18, p. 1. 

Pfeiffer, Kolle. Deut. med. Woch., 1896, p. 185. 

Rodet. Compt. Rend. Soc Biol., 1898, p. 756. 

Scholtz. Hvg. Rundschau, Bd. 8, p. 417. 

Schumacher. Zeit. f. Hygiene, 1899, Bd. 30, p. 364; Bd. 37, p. 323. 

Simon. Cited, Baumgarten's Jahresber., 1898, p. 336. 

JStahelin. Corresp. Schweizer Aerzte, 1898, p. 161. 

Stern. Cent. f. Bact., 1898, p. 673. 

Stewart. Amer. Public Health Assoc, vol. xxiii. p. 151. 

Thoinet. Semaine Med., 1896, p. 504. 

Thompson. Brit. Med. Jour., 1897, II., p. 1775. 

Ustvedt. Cited, Baumgarten's Jahresber., 1898, p. 342. 

V. d. Velde. Acad. med. de Belgique, 1897, Mar. 27. 

Villiers. Presse Med., 1896, p. 54. 

Wesbrook. Ref. Cent. f. Bact., 1898, p. 713. 

Widal. ' Soc. med. des Hop., 1896, p. 561. ^ Presse Med., 1897, I., p. c. 

Wilson. Medical News, 1901, vol. Ixxix. p. 81. 

Ziemke. Deut. med. Woch., 1897, p. 234. 

Zwpnik. Miinch. med. Woch., 1902, p. 1305. 



CHAPTER XV. 

MISCELLANEOUS INFECTIOUS DISEASES. 

SEPTICEMIA, PYEMIA, OSTEOMYELITIS. 

Red Cells. In no other disease do the red cells suffer destruction 
so constantly and to such an extent as in the toxemia of diffuse 
inflammation caused by the common pyogenic bacteria. This fact 
was very early noted, Braid\vood finding shrinkage of the red cells 
and absence of rouleaux, Mannassein remarking on their reduced 
diameter, and Quincke and Patrigeon observing extreme loss of Hb 
in cases of pyemia. 

Hayem and Toenissen placed the average loss of red cells in 
ordinary septic fever at 200,000 to 1,000,000 per week, while a con- 
tinuous diminution was found to persist as long as suppuration con- 
tinued. That the loss of red cells is often very much more rapid 
than Hayem supposed is shown by Grawitz's remarkable case, in 
which fatal puerperal sepsis combined with considerable hemorrhage 
reduced the red cells in about twenty -four hours to 300,000. 

Various forms of acute septicemia not infrequently reduce the red 
cells below 2,000,000, but none appear to act more violently than 
does puerperal or uterine sepsis. Hayem^ found only 1,450,000 
cells, 20 per cent. Hb, in a recent case of puerperal sepsis. Cabot 
reports 1,800,000 cells from a ''suppurating fibroid.'^ The writer 
found 1,600,000 cells and 20 per cent. Hb in a septic form of endo- 
metritis, not puerperal. 

When the suppurative process is localized the red cells are usually 
found to be only slightly affected, but with the first appearance of 
the '' septic ^^ condition the reduction of red cells promptly begins^ 
Roscher finding evidences of diminished concentration of the blood 
within the first few hours. In empyema, suppuration in wounds, 
pelvic abscesses, appendicitis, peritonitis, etc., the red cells are seldom 
markedly reduced, while the usual effects of fever are present and 
polycytliemia is often found. The Hb is, as usual, more susceptible 
than the red cells, and its loss is usually out of proportion to that of 
the red cells, the Hb-index being invariably low. 

Timofjewsky found that nucleated red cells appear promptly in the 
blood of dogs after moderate injections of pyogenic bacteria, in one 
instance reaching the enormous proportion of 25,698 per c.mm, Turk 
found considerable numbers of nucleated red cells in two cases of 
septicemia from cystitis. In cases of intense puerperal sepsis the 
writer has usually been able to find a few nucleated red cells, but 
they have never been very numerous. 

21 



322 THE ACUTE INFECTIOUS DISEASES. 

In chronic suppuration the red cells tend to diminish as long as the 
discharge continues. In a case of chronic empyema of one year's 
duration the writer found 1,800^000 cells and 25 per cent, of Hb, 
but an old pelvic abscess discharging a small quantity of pus for two 
years had induced very slight anemia. 

Morphological changes in the red cells in septicemia are usually 
present in moderate degree. Most cases show a pure type of sec- 
ondary chlorotic anemia with marked loss of Hb. The reduced 
diameter of the anemic cells^ previously noted, was distinct in the 
writer's case of septic endometritis, but did not approach the grade 
seen in some forms of primary disease of the blood. In severe cases 
many cells show granular degeneration, but polychromasia has, in 
the writer's experience, not been prominent. Marked differences in 
the size and shape of the cells do not appear, as a rule, until after the 
second or third week of a severe septic process. 

Leucocytes. A considerable number of cases of asthenic septi- 
cemia run their course without leucocytosis, or with distinct reduc- 
tion of white cells. Such cases have been reported by Limbeck, 
Krebs, Cabot, Turk, and, usually proving fatal, their significance is 
similar to cases of pneumonia, diphtheria, etc., with hypoleucocytosis. 
In Turk's case, and in one observed by the writer, while the leuco- 
cytes were subnormal, the proportion of polynuclear cells was very 
high. 

Da Costa reports absence of leucocytosis in twelve of twenty-one 
cases of severe septic processes, and the writer has observed a pro- 
longed puerperal case with severe chills in which leucocytosis failed 
to appear. 

The great majority of cases, however, show pronounced leucocy- 
tosis, which is usually in proportion to the severity of the disease. 
Among the reported cases showing no leucocytosis are doubtless 
some in which the examination of the blood was made during the 
antemortem decline in the number of leucocytes. 

Regarding the more minute factors determining the grade of leuco- 
cytosis little is definitely known, and the examination of the blood 
must be interpreted according to the circumstances in each case. 

While the r^de that suppuration induces leucocytosis is almost invari- 
able, it must he remembered that leucocytosis may promptly disappear 
lohen the exudation ceases, and thcd suppurations involving mucous sur- 
faces may induce very slight leucocytosis. 

The polynuclear leucocytes are almost always in high proportion 
in cases of sepsis, but Klein has recently described a case of hemor- 
rhagic septicemia^ with 76 per cent, of eosinophiles in the pleural 
exudate and 40 per cent, in the blood. 

Chemistry. The loss of Hb has already been mentioned as one 
of the chief alterations in the blood of septicemia. Its solution in 
the plasma and the occurrence of hemoglobinemia is observed in 
severe cases with rapid destruction of blood. In cases of puer- 
peral sepsis, or pyemia in infants, the solution of Hb may reach a 
very extreme grade. In a puerperal case the writer found the 
viscera discolored, and so great was the deposit of pigment that 



.MISCELLANEOUS INFECTIOUS DISEASES. 323 

the liver and spleen closely resembled, in gross and microscopic 
appearance, the organs of pernicious malaria. The increased 
globulicidal action of the sermn in these cases, to which the solu- 
tion of red cells must be referred, has been described by Maragliano 
and others. 

An increased tendency toward crystallization of the Hb has been 
noted by Bond, who, in examining fresh specimens, found a rich 
deposit of such crystals about the edge of the cover-glass. 

Roscher noted in severe cases a very rapid lowering of the specific 
gravity of the blood, beginning a few hours after the initial symp- 
toms. In fatal cases the dry residue of the whole blood fell to 15 
per cent., while in favorable cases the loss of solids was usually mucli 
less. This rapid and extreme loss of albumins Roscher and Grawitz 
regard as a valuable prognostic sign. The serum also usually showed 
a pronounced loss of albumin, proportionate to the severity of the 
septic process, its dry residue falling from 10.5 per cent, to a mini- 
mum of 6.25 per cent. Yet in a very severe case the dry residue of 
the serum was 13.1 per cent, of its weight, which Grawitz explains 
as resulting from the solution of Hb. 

In various forms of pyogenic infection Livierato found an excess 
of glycogen in the blood, even when the temperature was normal. 
Goldberger and Weiss also describe in the leucocytes during abscess- 
formation a reaction to iodine either in the form of a diffuse stain or 
a granular deposit. They also find many brownish staining extra- 
cellular granules after fractures, and believe that the somewhat 
obscure " iodine reaction ^' of the blood may be made of value in the 
diagnosis of abscess, fractures, etc. 

Bacteriolog'y. The frequency with which specific bacteria can be 
isolated from the circulating blood in cases of septic infection, in 
spite of the vast amount of study devoted to the subject, still remains 
a matter of doubt. 

There are, on the one hand, a large immber of studies of the blood 
in pyemia, septicemia, puerperal fever, osteomyelitis, etc., reporting 
the discovery of bacteria in a large proportion of cases, while in 
many others, reported by competent observers, very uniformly nega- 
tive results were obtained. 

On reviewing many of these reports it appears that the majority 
of them must be set aside as unreliable. 

Rosenbach, Garrod, Raskin, Brunner, Blum, Czerniewski, Eisel- 
berg, Cantu, Roux and Lannois, Bommers, Stern and Tlirschler, and 
others, all used blood squeezed from the finger, and when they 
attempted to demonstrate the same germ in the viscera after death, 
were not always successful. Many of their successful cultures were 
made only a few hours before death. When accurate details are 
given, as by Czerniewsky, it appears that contaminations by clearly 
non-pathogenic germs frequently occurred. 

On the other hand, ])rieger, drawing blood from a vein by a 
sterilized syringe, obtained negative results in five cases of puerperal 
sepsis. Sanger, by the same method, in three cases of osteomyelitis 
found staphylococcus aureus or aJbus in the blood, but cultures from 



324 THE ACUTE INFECTIOUS DISEASES. 

an inflamed joint gave only streptococcus pyogenes. Likewise Kraus 
reports six positive results in ten cases of puerperal sepsis, but one 
was examined postmortem, and two show^ed only staphylococcus albus. 
Cannon, who secured a number of successful cultures from the blood 
in puerperal sepsis, osteomyelitis, wound infection, etc., took some 
of his specimens from a puncture of the skin, and Petruschky, who 
usually obtained some bacteria, drew the blood through the " disin- 
fected " skin by means of a wet cup. Sittmann, accepting as genuine 
the results of previous investigators, and adding nine positive cases 
of his own, concludes that in septicopyemia the bacterial agent is 
always to be found in the blood, and that its presence does not insure 
a fatal issue. 

Somewhat striking conclusions may be drawn from the reports of 
Bertelsman, who secured fifty-four negative and forty-seven positive 
results from examinations in 101 cases of various forms of suppura- 
tion. In twenty-seven cases the streptococcus was obtained, and in 
fifteen staphylococci. Important features of his study were the uni- 
formly positive cultures in osteomyelitis (six cases), the demonstration 
of bacteremia in panaritium, and in five of nine cases of urethral fever, 
in phlegmonous erysipelas, and in three cases of cryptogenic strepto- 
coccus septicemia which recovered, while in several instances it w^as 
shown that bacteria were present in the circulating blood for short 
periods and in rapidly decreasing numbers. In the absence of much 
greater detail than accompanies the report, such results cannot be 
accepted without confirmation. 

Old observers, as Kuhnau, do not accept the conclusions of Sitt- 
mann and do not admit much significance in the isolation from the 
blood of staphylococcus albus or the colon bacillus. Kuhnau examined 
the blood repeatedly in twenty-three cases of septicopyemia, nineteen 
of which were fatal. In two streptococcus pyogenes was obtained, in 
one staphylococcus aureus. Several cultures gave non-pathogenic 
germs, among them staphylococcus albus, which was obtained from 
the blood, but not from the abscesses after death. The only success- 
ful cultures were made shortly before death, or in one case during a 
chill. 

White also found streptococcus pyogenes only three times and 
staphylococcus aureus once in eighteen fatal cases of sepsis. 

The results of Kuhnau's study cannot fail to raise the suspicion 
that many investigators have been too lax in technique, or have not 
fully identified their species. 

From the review of the above studies the writer draws the follow- 
ing conclusions : 

1. The only reliable method of obtaining blood for bacteriological 
examination during life is to draw it from a vein, in quantity not 
less than 5 c.c, through the thoroughly sterilized, or, better, the 
incised skin, by means of a sterile syringe or aspirator. 

2. In the great majority of cases of local or general septic infec- 
tion, septicopyemia, septicemia, pyemia, diffuse suppuration, osteo- 
myelitis, etc., bacteria are present in the circulating blood only for 
short periods and at infrequent intervals, most frequently during chills. 



MISCELLANEOUS INFECTIOUS DISEASES. 325 

3. A few hours before death from septic infection, various bac- 
teria, some of which may not be active in the original process, make 
their way into the circulation. 

4. In a very moderate number of cases of septic infection, esi)e- 
cially those which are not attended by local abscess formation, the 
bacterial agent may be isolated from the blood during the progress 
of the disease. 

APPENDICITIS. 

Red Cells. From the observations of Da Costa in 139 cases it 
appears that anemia of moderate grade exists in nearly all cases of 
appendicitis. It is least marked in catarrhal cases, in thirty-eight 
of which Da Costa found an average of 4,180,000 cells, with some 
exceptions showing much greater loss, while the Hb commonly 
registered 20 to 40 per cent, below normal. Anemia is most marked 
in cases with abscess of long standing, in which the toxemia fre- 
quently causes a loss of 25 to 45 per cent, or more of Hb and a re- 
duction of the red cells below 4,000,000. In Da Costa's series a 
reduction to 2,000,000 red cells was twice observed, once with a 
catarrhal and once with a suppurative lesion, while more than 
5,000,000 cells were found in twenty cases. 

Leucocytes. The behavior of the leucocytes is extremely vari- 
able. While catarrhal or simple exudative appendicitis usually fails to 
sliow leucocytosis. Da Costa found over 15,000 cells in five of forty- 
five such cases, average 8987, and once 17,100. This leucocytosis 
he attributes to local peritonitis or to conditions apart from the 
ap])endicitis. 

With necrotic lesions, abscesses, gangrene, and general peritonitis 
there is well-marked leucocytosis in nearly all cases, except in the 
fulminant and asthenic type of the disease, in which the leucocytosis 
may fail. The majority of all cases fall in this category, as did 
thirty-three of seventy-two reported by Cabot, and ninety-t^vo of 139 
by Da Costa. While most of these cases show more than 1 5,000 white 
cells, and many more than 20,000, a considerable number fall below 
15,000 within the limit frequently seen in simple exudative ])rocesses. 

As in pneumonia, etc., very marked or very slight leucocytosis 
may be found in grave cases calling urgently for operation, while 
the sudden transformation M^hich follows perforation from a necrotic 
process of small extent commonly fails to give warning by a disturb- 
ance of the leucocytes. Cabot reports four cases of general periton- 
itis without leucocytosis and two with slight increase (14,800, KkOOO). 

In following the course of appendicitis the daily examination of 
the blood may bring to light some important considerations. 

A steadily increasing leucocytosis usually indicates an extending 
local process. 

After an abscess has been formed the leucocytes commonly lluctuate 
between distinctly high limits, risino- abruptly if peritonitis deveh^ps. 
As the abscess becouies walled off the leucocytes slowly diminish, 
and when pus is evacuated a favorable course is indicated by a ra]>id 
decrease of leucocvtes. 



326 THE A C UTE INFECTIO US DISEA SES. 

In chronic cases without active formation of pus the leucocytes 
are usually subnormal (Bloodgood). 

It, therefore, appears that the interpretation to be placed upon 
the examination of the blood in appendicitis, especially in its early 
stages, is extremely variable. With leucocytosis ranging between 
8000 and 16,000 cells, the condition may rather frequently be : 
(1) simple exudative appendicitis ; (2) necrotic inflammation with 
perforation and abscess ; (3) a large abscess ; (4) general peritonitis. 

The blood changes follow no definite rule in those dangerous forms 
of the disease which pursue a mild course for a time, but suddenly 
develop peritonitis from perforation. Nor can the question of opera- 
tion in frank cases be decided from the examination of the blood 
alone, which indicates only what damage actually exists, while the 
operation is intended to meet the conditions which may later arise. 
One of Cabot\s cases with 33,000 white cells recovered without inter- 
ference. After the period of invasion is passed and the character of 
the lesion established, the indications of the blood have proved much 
more reliable. 

In differential diagnosis a positive conclusion seems to be warranted 
only in those cases which show well-marked leucocytosis, from the 
presence of which it is possible to rule out nearly all forms of typhoid 
fever, most but not all cases of fecal impaction, and nearly all forms 
of abdominal neuralgia. Hubbard, Da Costa, and Cabot have offered 
some very practical comments on the limitations of blood analyses 
in this field. 

ABSCESS FORMATION. 

Active suppuration in a confined space is almost invariably accom- 
panied by distinct leucocytosis. Cabot has remarked on the high 
leucocytosis usually observed with very limited suppurative foci in 
subcutaneous, submucous, or interstitial connective tissues, and 
reports very considerable increase of white cells, with furuncle, car- 
buncle, and abscess of vulva, vagina, middle ear, uterus, Fallopian 
tube, ovary, lung, brain, parotid gland, neck, and in pectoral, psoas, 
and perinephritic regions. The writer's experience in a considerable 
variety of such conditions fully accords with these reports, leucocy- 
tosis having been present in the active stages of all such processes, 
but subsiding slowly or rapidly after operation or after the exudative 
process had ceased. An important exception to the rule was found 
in abscess of the liver with mucopurulent exudate. (See Liver.) 

Glycogenic degeneration of the leucocytes, according to Lockers 
observations, occurs in considerable degree with all large abscesses, 
but is not a reliable indication of the presence of pus, since it may 
be absent with small abscesses, and disappears in forty- eight hours 
after the abscess is drained. 

ERYSIPELAS. 

A slight diminution of red cells and Hb was observed in severe 
cases by Malassez, Hayem, and Reinert. In mild cases the fibrin 



MISCELLANEO US INFECTIO US DISEASES. 327 

is not affected, but in severe forms of the infection its formation is 
much increased (Turk). 

Leucocvtosis occurs in nearly all cases, but Rieder reported one 
instance of facial erysipelas with a temperature of 39° C. and 6800 
white cells. Turk observed one case of considerable extent with 
temperature 38.5° to 40.2° and the leucocytes between 7000 and 
8900. Later the temperature rose to 40.5° and the leucocytes to 
10,100. Zappert, also, observed two febrile cases with subnormal 
numbers of white cells (5500 to 6500). Hay em found between 
7000 to 8000 leucocytes in very mild cases, but 12,000 to 20,000 
when the rash was extensive. 

Most of the cases of Pee, Rieder, Ehrlich, Limbeck, and Cabot 
gave leucocytosis of moderate grade, but in proportion to the severity 
of the disease. Higher leucocytosis was observed by Halla in uncom- 
plicated facial erysipelas, and in a case complicated by pneumonia 
(23,000). Suppuration raised the count to 39,600 in a case of Eein- 
ert, and to 59,400 in one of Epstein. Chantemesse and Rey found 
that the leucocytes and the temperature vary as a rule together, 
although in some cases high fever was unaccompanied by leucocy- 
tosis. 

AYhen the total increase is considerable the polynuclear cells are 
much increased in proportion, but with slight increase the polynuclear 
cells are usually unaffected. Eosinophiles are usually diminished or 
absent (Zappert, Turk). Scanty myelocytes may also be found dur- 
ing the active stages, 5 per cent, of these cells having been recorded 
by Turk. 

Negative bacteriological examinations of the blood in erysipelas 
are reported by Petruschky in three cases and by Kraus in one case. 
Bertelsman had negative results in three severe cases, and positive 
cultures in two fatal cases of phlegmonous type. 

ACUTE RHEUMATISM. 

A much increased formation of fibrin has been noted by many 
observers, Halla, Hayem, Berggrun, Turk. Garrod failed to find 
any uric acid in the blood of acute rheumatism, and Salmon demon- 
strated the absence of lactic acid. 

Red Cells. It is a general clinical rule that patients who pass 
through an attack of acute rheumatism become distinctly anemic. Li 
many cases of ordinary severity the loss of red cells is slight, while 
the Hb falls to 80 or 65 per cent. 

In more severe eases Hayem seldom found more than 4,000, (H'tO 
cells. Sorensen found an average of 4,160,000 in eight ca^^es. In 
prolonged and relapsing cases the red cells not infrequently fall 
slightly below 4,000,000. Yet in few of the reported studies are the 
examinations sufficiently extensive to show that such anemia is 
referable to the acute disease. Turk, while admitting the usual 
presence of anemia even during the febrile period, saw a distinct 
increase in red cells beginning with defervescence, and in Cabot's 
cases it does not appear either that there was any uniform loss of red 



328 THE ACUTE INFECTIOUS DISEASES. 

cells or that the cases of long standing were invariably the more 
anemic. It seems, therefore, that the severity of post-rheumatic 
anemia has been overestimated. 

The Ho suffers more severely and much more constantly than the 
red cells. Cabot's average in thirty-one cases was 67 per cent., and 
a few cases fell below 60 per cent., while Turk found between 60 and 
80 per cent. Prompt use of salicylates prevented the loss of Hb in 
a case of Lichtenstern's, and apparently also in one of Cabot's. 
Da Costa reports two very anemic cases with 26 and 30 per cent, of 
Hb, and 1,240,000 and 1,600,000 red cells. 

In convalescence the restoration of Hb remains considerably behind 
that of the red cells. 

Leucocytes. In mild cases without exudation there is usually no 
distinct leucocytosis (Pee, Rieder). When fever and swelling of 
joints exist there is almost always an increase to 10,000 or 15,000 
cells. Turk insists that when the leucocytes reach 20,000 or more 
there are nearly always complications, such as pleurisy, pericarditis, 
or pneumonia. Hayem also found 17,000 to 18,000 cells in moder- 
ately severe attacks, and as high as 25,000 only in extremely severe 
and cerebral types of the disease. Cabot reports 21,000 to 31,000 
cells in six cases, one complicated by acute endocarditis, while in the 
others no complication was mentioned. The writer, from the exami- 
nation of forty cases, in 1893, can support Turk's statement, having 
found signs of pneumonia, or pericarditis, or hyperpyrexia, whenever 
the leucocytes rose above 20,000. The pneumonic signs, however, 
were not always those of complete consolidation. 

With defervescence the leucocytes promptly fall to normal, and in 
relapses are much less affected than by initial attacks (Turk). 

Types of Leucocytes. When the white cells do not greatly exceed 
10,000, the proportions of the various forms are not much disturbed. 
With distinct leucocytosis the proportion of polynuclear cells rises to 
a considerable height. Eosinophile cells are absent only in the 
early stages ; later, in spite of fever and exudation, they are always 
present in moderate numbers, while after defervescence most 
cases show a distinct tendency toward eosinophilia (Turk, Achard, 
Loeffler). In one of Turk's cases there were 13.8 per cent, of eosino- 
philes, and in another 8.33 per cent, shortly after defervescence. 
This observer believes that a high proportion of eosinophile cells 
during the febrile period is a good prognostic sign, and occurs 
principally in self-limiting cases. 

Bacteriology. In several studies, reviewed by Sittmann, various 
pathogenic bacteria were obtained from the circulating blood, but 
these cases have later been classed as examples of septicemia and not 
of articular rheumatism. The principal bacterioloa^ical studies of the 
blood of acute rheumatism are those of Sittmann, Singer, Kraus, and 
Kuhnau. Sittmann obtained negative results from repeated cultures 
in five cases, and Kraus in twelve cases. Singer conducted an elab- 
orate study of the blood and urine in sixty cases, but while he found 
staphyloGOGGus al'->ns in several instances, this germ was probably a 
contamination from the skin. In one case streptococcus pyogenes was 



MISCELLANEOUS INFECTIOUS DISEASES. 329 

isolated, but the history shows the patient to have been suffering 
from liemorrhagic septicemia and endocarditis. 

Es^en more conchisive were the totally negative results obtained 
by Kuhnau in sixty-seven cases representing all types of the disease 
and many complications. 

In the etiology of rheumatism several theories are at present 
actively maintained. Singer urgently claims that the disease is a 
mitigated form of pyemia from infection by streptococcus or staphylo- 
coccus pyogenes. A considerable number of observers, including 
Ley den, Triboulet, Wasserman and Meyer, and Poynton and Paiue, 
have isolated from the blood and tissues a diplococcus which repro- 
duces the disease in rabbits more or less perfectly and which they 
regard as the etiological agent. Singer thinks that this diplococcus 
is the streptococcus pyogeneSy but it decolorizes by Gram\s method. 

Achalme and various other French observers have endeavored to 
prove the importance of an anaerobic spore-bearing bacillus obtained 
in several cases from the heart's blood and tissues. Others regard 
this bacillus as a contamination from the media. Predetchensky, 
who found the streptococcus in the blood in two of five cases, failed 
to secure any trace of Achalme's bacillus in large quantities of blood 
with liquid media and complete anaerobiosis. It is generally believed 
that bacterial invasion is a secondary phenomenon, and that Avhile 
the disease may be of bacterial origin the circulating blood \<^ nearly 
always sterile. At present it is impossible to decide between the 
claims of Singer and the results of Kuhnau, and those of Poynton 
and Paine, Triboulet and Coyon, or Achalme. 

TONSILLITIS. 

Follicular tonsillitis usually causes moderate leucocytosis, seldom 
rising above 15,000 (Halla, Pick, Pee), yet in mild cases it may 
be absent (Cabot). In phlegmonous tonsillitis more marked leuco- 
cytosis, reaching 20,000 cells or more, usually occurs (Pee, liieder). 

The leucocytosis is generally more marked than in diphtheria with 
equal constitutional disturbances (Pee). 

WHOOPING-COUGH. 

Meunier has observed, in thirty cases of pertussis in children of 
various ages, a pronounced or extreme leucocytosis which ^' far 
exceeds the increase found in any other afcbrUe disease of the respira- 
tory passages.^^ 

The grade of leucocytosis varies with the age of the patient, being- 
most marked in children under four years, and usually reaching a 
slightly lower figure in children from four to seven years. It appears 
in the catarrhal stage before the characteristic cough, when its demon- 
stration may be made of diagnostic value, and disappears slowly with 
the improvement of the disease. It is little infiuenced by complica- 
tions. The average leucocytosis was 27,800, but in several cases 
40,000 cells were found, and in one 51,160. The lowest tigurc 



330 THE ACUTE INFECTIOUS DISEASES. 

obtained daring an active period was 15,500. The proportion of 
lymphocytes was always high, averaging 53.8 in a portion of the 
cases, while the polynuclear cells maintained a low average (39 per 
cent.), and the eosinophiles were scarce or normal in number. 
Meunier refers the lymphocytosis to hyperplasia of bronchial lymph 
nodes. 

De Amicis and Pacchioni also report marked leucocytosis in 
whooping-cough, beginning in the first days of the disease, reaching 
its height in the spasmodic stage, and being sometimes prolonged 
after the cessation of the typical cough. Cabot found 12,600 white 
cells and 78 per cent. Hb in a girl aged six years. In four cases in 
children between the ages of two and six years Stengel and AYhite 
noted leucocytosis — 12,145 to 34,667 — of which the polynuclear cells 
constituted 30 to 40 per cent. 

INFLAMMATIONS OF SEROUS MEMBRANES. 
Pleurisy, Pericarditis, Peritonitis. 

Serous inflammations of the large serous membranes usually cause 
a slight increase of leucocytes in the blood during the acute febrile 
stages. Thus Hayem found between 7500 and 12,000 leucocytes in 
acute pleurisy ; Rieder 11,000 to 13,000 ; and some of Cabot's early 
cases registered as high as 15,000. Higher leucocytosis belongs to 
the more severe inflammations, with temperatures reaching 101° to 
104° F. In two cases of serofibrinous pleurisy Limbeck found, 
with a temperature of 38.8° C, 18,000 to 19,000 leucocytes, and 
with a temperature of 41.5° C, 22,000 cells. The grade of leuco- 
cytosis excited by fibrinous pleurisy, pericarditis, etc., has apparently 
not been determined. The inflammation stands in an intermediate 
position in point of intensity. 

With purulent processes the leucocytosis is usually much higher. 
In 1893 the writer found no difference in the leucocytosis of pneu- 
monia from that of idiopathic empyema and purulent pericarditis. 
All the cases of pericarditis were complicated by pneumonia or rheu- 
matism and gave very high counts (maximum 60,000). The writer 
has seen one case of very rapidly fatal empyema, yielding streptococcus 
pyogenes in cultures, in which there was scanty purulent exudate and 
slight and diminishing leucocytosis. 

In purulent peritonitis, also, leucocytosis is not infrequently absent. 

After the exudative process has ceased the leucocytosis subsides, 
very rapidly in the case of serous exudates and usually more slowly 
with purulent processes. The majority of serous effusions are there- 
fore encountered, as in Halla's and Cabot's cases, when the leucocytes 
are normal in number ; nor is it rare to find extensive empyema with 
no excess of white cells in the blood. 

Tuberculous inflammations of serous membranes, when pure and 
uncomplicated, are usually not accompanied by leucocytosis. 

In serous pleurisy it is seldom possible to distinguish the quiescent 
stages of simple serous effusions from beginning tuberculous exudates, 



MISCELLANEOUS INFECTIOUS DISEASES. 331 

and the examination of the blood cannot prove of much value in 
diagnosis. 

Further considerations of the changes in the blood in inflammations 
of serous membranes is to be found in the sections dealing with 
appendicitis, rheumatism, tuberculosis, etc. 

GONOREHEA. 

In acute gonorrheal urethritis the red cells remain unaffected. A 
moderate leucocytosis is usually observed in severe febrile cases, and 
is markedly increased by many complications, including cystitis, 
epididymitis, orchitis, etc. 

The polynuclear cells are in the usual excess, while eosinophiles, 
although sometimes very abundant in the urethral discharge (Bett- 
man), usually remain within moderate limits (0.5 to 11.5 per cent.) 
in the blood (Vorbach). Bettman, however, while finding that there 
is no relation between the eosinophile cells of the discharge and 
those in the blood, believes eosinophilia is usually present in gonor- 
rhea, especially in posterior urethritis. He found 25 per cent, in the 
Wood in a case of gonorrheal epididymitis. 

In gonorrheal rheumatism the changes in the blood are similar to 
those of the idiopathic joint affections. 

The gonococcus has several times been isolated from the blood in 
gonorrheal endocarditis (q. v.). Panichi, in two cases of gonorrheal 
rheumatism without endocarditis, reports the isolation of the gono- 
coccus from blood sowed on human blood serum. He believes that 
the culture of the blood in order to be successful must be made at 
the time of invasion of the rheumatic symptoms. 

YELLOW FEVER. 

From Jones' interesting observations about yellow fever, it would 
appear that anemia is infrequent, that fibrin formation is deficient, 
that the globulicidal action of the serum is very greatly increased, 
and that cholemia is responsible for some of the changes observed in 
the red cells before and after shedding. ^^ When a drop of blood 
from a yellow-fever patient falls upon blotting-paper, a dark, brownish 
ring due to diffusion of bile-stained plasma spreads about the central 
mass of blood cells '' (Jones). 

Pothier examined in some detail the blood of 154 cases. The red 
cells never fell below 4,280,000, and in one fatal case were normal. 
The Hb suffered a considerable loss during the course of the disease, 
registering between 50 and 72 per cent. In the above fatal oases iH> 
per cent, of Hb was found. The restoration of the Hb was slow. 

llorphological changes in the red cells were usually absent, but the 
presence of normoblasts was noted in a few specimens. 

The lemocijtes fell between 4()()0 and 20,000. The polynuolenr 
cells were found in high proportions in some of the slides from those 
cases examined by Cabot, while in others their proportions wore 
normal. Eosinophiles were very scarce and myelocytes wore found 



332 THE ACUTE INFECTIOUS DISEASES. 

ill two cases. The writer examined dry specimens of the blood of 
two rapidly fatal cases of yellow fever brought from Rio Janeiro by 
Dr. J. M. Masury, and noted slight hemoglobinemia and hypoleuco- 
cytosis. 

Pothier tested the action of the serum of some of his patients on 
cultures of Sanarelli's bacillus^ but the results did not indicate the 
presence of any specific power in the blood. 

Archinard and Woodson claim to have found the blood in yellow 
fever to agglutinate the bacillus of Saranelli in 75 per cent, of the 
cases. Reed and CarrolP have shown, however, that while this 
reaction occurs in a small proportion of cases (34 per cent.), it is in 
those same cases exhibited also with the bacillus of hog-cholera, with 
which they identify the bacillus of Sanarelli. 

Through the labors of Reed, Carroll, Agramonte, and Lazear, the 
importance of Sanarelli's bacillus in yellow fever has been set aside, 
and it has been shown that the specific virus of the disease is present 
in the circulating blood and is transferred from one subject to another 
by means of the mosquito, cidex fasclatics. 

An interval of about twelve days or more after contamination 
appears to be necessary before the mosquito is capable of carrying 
the infection. They succeeded in producing yellow fever in a series 
of non-immune subjects through the agency of mosquitoes under con- 
ditions precluding the possibility of error. They also transferred 
the disease by injections of blood taken during the first and second 
days of illness.^ The blood itself was found sterile. In three cases 
blood heated for ten minutes at 55° C. failed to cause any symptoms 
when injected in doses of 1.5 c.c. in non-immune subjects. Of three 
subjects receiving injections of 1.5 c.c. of yellow-fever serum passed 
through a Berkfeld filter two developed the disease. From one of 
these two cases serum was obtained and injected into a non-immune 
subject who also developed the disease. Reed and Carroll, therefore, 
conclude that the contagium of yellow fever is a very minute organ- 
ism capable of passing through a Berkfeld filter. 

TYPHUS FEVER. 

In four cases the writer found between 5000 and 9000 leucocytes. 
The patients were adults, the examinations were made during the 
high fever of the early period of the disease, and at least two of the 
patients died. 

Tumas followed one fatal case during a three weeks' course, observ- 
ing a steady reduction of red cells from 4,400,000 to 3,100,000, of 
Hb from 80 to 50 per cent., and hypoleucocytosis 9600 to 1600. 

EPIDEMIC INFLUENZA. 

The scanty reports of the condition of the blood in epidemic influ- 
enza indicate that the disease in uncomplicated form fails to cause 
leucocytosis. This fact, while in accordance with the catarrhal 
character of the essential lesions, is somewhat difficult to reconcile 



MISCELLANEOUS INFECTIOUS DISEASES. 333 

^Yitll the acute infectious nature of the disease. Grippe appears to be 
the only bacterial disease, beginning acutely with marked chill, which 
fails to induce leucocytosis. 

The absence of leucocytosis in grippe was first demonstrated by 
Rieder/ who, in seven cases, found that the white cells at the acme of 
the disease were reduced in number (7000 to 2800). In the catarrhal 
pneumonia which complicates the disease and which is distinguished 
by signs of incomplete consolidation, he found little or no leucocy- 
tosis (maximum, 13,000). In lobar pneumonia following grippe the 
usual leucocytosis was observed. In 1893 the writer found no differ- 
ence in the leucocytosis of lobar pneumonia following grippe from 
that of primary pneumonia. Cabot reports the examination of the 
blood in sixty-seven cases, most of which showed normal or reduced 
numbers of white cells, and when there was leucocytosis (maximum, 
14,000) complications were usually present. 

Bacteriological Examination. In a considerable proportion of 
cases Canon, Klein,- Hirschfeldt, Brnschettiui, and others have 
obtained from the blood cultures of what they believed to be 
Pfeiffer's bacillus. Successful cultures are sometimes found to have 
been secured from blood squeezed from the finger-tip, as by Slawyk. 

Pfeiffer and Kruse and others were unable to isolate the bacillus 
of influenza from the blood, and denied the identity of some of the 
germs obtained from the blood by others. 

Recently Kuhnau has added twelve negative results, and there 
seems little reason to doubt that the bacillus of influenza has no 
special capacity to invade the blood stream. 

RABIES. 

Friedrich,^ in 1869, observed an increase of white blood cells 
eighteen hours before death. 

Courmont and Lesieur have recently followed the leucocytes in 
the disease in both man and animals. Rabies in man is apparently 
unaccompanied by leucocytosis until a few hours before death, when 
a terminal increase, principally of polynuclear cells, appears. 

In two cases one hour before death 21,000 and 24,000 cells were 
counted, while in three cases the antemortem proportion of poly- 
nuclear cells was 83 to 88 per cent. In experimental rabies no 
leucocytosis developed until nervous symptoms appeared. 

In both man and animals, however, an excess of polynuclear cells 
was found before any distinct increase in their numbers. In spon- 
taneous rabies in dogs (five cases) there was leucocytosis, with 88 to 
98 per cent, of polynuclear cells, twenty -four to forty-eiglit hours 
before death. 

TETANUS. 

Cabot reports 70 per cent, of lib, 11,900 leucocytes, and ]>ersist- 
ence of eosinophile cells, in a fatal case of tetanus treated by antitoxin, 
and 19,()00 in a second case. 



334 THE ACUTE INFECTIOUS DISEASES. 



BUBONIC PLAGUE. 

Coagulation of the blood failed entirely in ten of twelve fatal cases 
in which the blood was collected in sealed tubes by Cor thorn, while 
in two other fatal cases the clot was imperfect. 

The Austrian Pest Commission found 65 to 80 per cent. Hb in 
the majorty of cases. Leucocytosis was always present, but not 
in excessive degree, the numbers varying between 12,000 and 
28,000. 

Aoyama, in 1895, examined the blood of many cases, reporting 
four in full. The red cells varied from 4,400,000 to 8,100,000, the 
latter in a case which recovered, and in the report of which no cause 
of polycythemia is apparent. The Hb was normal. The leucocy- 
tosis also was reported to have reached a very high grade. Poly- 
nuclear cells made up the bulk of the increase, but large and small 
lymphocytes were numerous, and eosinophiles scarce. 

Zabolotny studied the reaction of the blood serum on cultures of 
the bacillus. During the first week no effect was observed even with 
a dilution of 1:6; in the second week reactions were obtained with 
dilutions of 1 : 10 ; in the third week with 1 : 25 ; in the fourth 
week with 1 : 50. The reaction was most marked in the severer 
cases, and the blood serum of the cadaver was inert. 

Kitasato, in 1894, reported the demonstration of bacillus pestis in 
twenty-five of twenty-eight cases in smears of blood squeezed from 
the finger-tip, but this method gives no reliable indication of the 
presence of the organism in the circulating blood. Many later 
observers, relying on the same method, have drawn erroneous con- 
clusions regarding the occurrence of this bacillus in the blood. 
Thus, Eees found it in the smears of the blood when cultures of the 
blood drawn aseptically were sterile. The Austrian Commission 
and others came to the conclusion that the bacteriological examina- 
tion of blood smears in plague is not only unreliable, but fallacious 
and mischievous. They placed little diagnostic value even on the 
proper bacteriological examinations of the blood. 

MALTA FEVER. 

The hemorrhages which mark the severer forms of this malady 
commonly give rise to severe anemia. Bruce places the average 
number of red cells at 3,500,000, and reports the absence of leuco- 
cytosis and occasional presence of free pigment in the blood. In 
a prolonged case without hemorrhages Musser and Sailer found 
5,050,000 red cells, 60 per cent. Hb, 11,564 leucocytes, all varieties 
being in normal proportions. 

Wright and Smith found that the blood serum of cases of Malta 
fever agglutinates cultures of bacillus meUtensis, and diagnoses of the 
disease have been made by this method by Musser and Sailer, Cox, 
and others. A dilution of serum 1 : 50 should give a prompt reac- 
tion, while typhoid serum has no effect. 



MISCELLANEOUS. INFECTIOUS DISEASES. 335 



ACTINOMYCOSIS. 

The writer found 21,500 leucocytes in a case of pulmonary actino- 
mycosis, clinically resembling acute phthisis, and Cabot reports a 
case of actinomycosis of liver with 3700 white cells. 

The markedly purulent character of the exudate excited by the 
ray fungus explains the grade and character of the leucocytosis. 
Bierfreund found marked chlorotic anemia in actinomycosis, the Hb 
registering 30 to 50 per cent. 

GLANDERS. 

Cabot refers to a case of acute glanders in which the fibrin was 
increased, the Hb normal, and the leucocytes varied between 11,600 
and 13,600, 86 per cent, of which were polynuclear. Coleman and 
the writer reported an acute case with extensive pulmonary lesions, 
in w^hich the leucocytes steadily numbered 13,000. Bacillus mallei 
was isolated from the blood three days before death. 

Duval isolated the bacillus of glanders from the blood during life, 
and Noniewitch reports that in fatal cases in horses the bacilli can 
be found in the circulating blood, usually within the leucocytes. 

ANTHRAX. 

Anthrax in some lower animals frequently develops into a pro- 
nounced bacteremia early in the disease. Man, however, usually 
exhibits only a moderate grade of susceptibility to the infection and 
the majority of cases recover after excision of local foci of infection. 
Although it is probable that in the severe septicemic forms of the 
disease anthrax bacilli may multiply in the general blood stream 
early in the disease, the literature appears to contain very few re- 
ports of competent bacteriological analyses of the blood in such con- 
ditions. The rather frequent impression that the diagnosis of anthrax 
can be made by morphological examination of a drop of blood from 
the general circulation is almost entirely without foundation, as the 
great majority of the cultures of the blood, even in severe cases, have 
been found sterile. Only in the late stages of some septicemic cases 
in man do the bacteria invade the circulation and yield positive cul- 
tures of the blood. Such a case is that of Blumer and Young, 
who report successful cultures, and claim to have identified the 
germ in blood smears during life, but the time before death was not 
stated. 

Antemortem invasion of the blood by anthrax in man is apparently 
not much if any more abundant than with some other infections, 
and even postmortem cultures are frequently negative. 

Detailed clinical examinations of the red cells and leucocytes in 
the blood of anthrax are still wanting. 



336 THE ACUTE INFECTIOUS DISEASES. 

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Aoyama. Mittheil, a, d. kaiserl. Japanisch. Univers., 1895, Bd. 3, No. 2. 

Bein. Zeit. f. klin. Med., Bd. 17, p. 545. 

Bertelsman. Arch. f. kl. Chir., Bd, 67, p, 940, 

Bettman. Archiv f. Derm, und S\Tph., Bd. 49, p. 227. 

Bierfreund . Archiv f. Chirurg., Bd. 41. 

Blum. Miinch. med. Woch., 1893, p. 297, 

Blumer, Young. Johns Hopkins Bulletin, 1895, p. 12' 

Bommers. Deut. med. Woch., 1893, p. 552. 

Bond. Lancet, 1887, II., pp. 509, 557, 

Braidwood. On Pvemia, etc, London, 1868. 

Brieger. Charite-Annalen, 1886, p, 198, 

Bruce. Lancet. 1892, II., p. 1101. Annal. de I'lnstitut Pastem% 1893. 

Brunner. Wien. klin. Woch., 1891, p. 391. 

Bruschettini. Rif. Med., 1893, Xo. 186. 

Cannon. Deut. Zeit. f. Chirurg., Bd. 33, p. 571. 

Canon. Virchow's Archiv, Bd. 131, p. 401. 

Cantu. Rif, Med., 1892, IL, p. 243, 

Coleman, Ewing. Jour of Med. Research, vol. ix., p. 223. 

Corthorn. Brit, Med, Jour,, 1902, I., p. 1143. 

Courmont, Lesieur. Jour, de Ph^'s, et de Path., 1901, p. 599, 

Cox. Philadelphia Med, Jour,, a'oI, iv, p, 491. 

Czerniewsky. Archiv f. Gynecol., 1888, Bd. 33, p. 73. 

De Ajnicis, Pacchioni. Ref. in Amer. Jour. Med. Sci., vol. cxix. p. 599. 

Duval. Archiv. de Med. exper., 1896. p. 361. 

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Epstein. Allg. Wien. med. Zeit., 1889, Xo. 43, 

Friedrich. ^ Arbeit, a. d. kaiserl. Gesundheit., 1890, p. 250. - Schmidt's 
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Halla. Zeit. f. Heilk., Bd. 4. 

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Krebs. Diss, Berlin, 1893. 

Kruse. Cent, f, Bact., Bd. 7, p. 657. 

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3IISCELLANE0US INFECTIOUS DISEASES. SS7 

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Zabolotny. Compt. Rend. Soc. Biol, 1897, p. 520. 



22 



CHAPTEK XVI. 

SYPHILIS, TUBERCULOSIS, LEPEOSY. 
SYPHILIS. 

Very accurate conclusions regarding the state of the blood in 
syphilis were reached by Becquerel and Rodier^ who stated that a 
moderate grade of anemia were to be found in the great majority of 
cases, that as long as the disease progressed without complications 
the blood maintained a high or normal standard, and that if the 
course of the disease were prolonged there was a loss of red cells. 
They noted also that the abuse of mercury might lead to the same 
changes. The resemblance of the anemia of syphilis to that of chlo- 
rosis was also early recognized, especially by Ricord, and this belief 
was later supported by analyses of the blood by Grassi, Wilbouche- 
witch, Keyes, Laache, Malassez/ Gaillard, and others, who found in 
the secondary and tertiary stages of most cases a loss of red cells and 
Hb. Keyes was the first to point out that mercury in small doses, 
while curing the disease, increases the red cells. 

The grade of anemia observed was usually moderate, the majority 
of cases showing slight loss of red cells, which, however, sometimes 
fell to 3,000,000 to 4,000,000. The Hb was usually found dimin- 
ished more than the cells, especially by Lezius, who claimed that the 
only essential lesion of the blood in syphilis is a loss of Hb. Other 
patients appeared to have normal blood, and Sorensen in tvfenty cases 
failed to detect any distinct anemia. On the other hand, Miiller 
reported cases in which all the typical lesions of pernicious anemia 
were present, and in one of his cases the red cells fell to 428,100. 
Other such cases are reported by Ponfick, Kjerner, Klein, Laache, 
Fisischella (cited by Dominici). 

It was thus established that syphilis in some stages and in some 
patients may entirely fail to reduce the red cells, while in others 
grave pernicious anemia must be charged to its action. The later 
studies have been concerned with the more detailed course of the 
blood changes in the disease, and have been contributed principally 
by Anc, Lezius, Bieganski, Konried, Rille, Loos, Justus, and Riess. 

From these contributions it appears that the blood suffers in a 
somewhat uniform degree in the several stages of uncomplicated 
syphilis, but unfavorable conditions and abuse of mercury may greatly 
aggravate the changes observed. 

Primary Stage. During the first four to seven weeks after infec- 
tion the red cells do not diminish perceptibly in number (Lezius, 
Konried, Oppenheim and Lowenbach) unless there is fever or some 
other disturbing factor, when a moderate decrease may be noted from 



SYPHILIS, TUBERCULOSIS, LEPROSY. 339 

the first (Stoukovenkoff). No doubt, as Hayem says, these disturb- 
ing factors are frequently present, and it still remains uncertain 
whether syphilis alone affects the number of red cells during the first 
few weeks. The majority of observations indicate that it does not, 
but Eiess came to a contrary conclusion, while Bieganski found 
uniform polycythemia in the early stages of syphilis. Recently 
Oppenheim and Lowenbach in thirty-four cases failed to find any 
distinct reduction in red cells. 

The Hb is almost invariably diminished from the first, a loss of 
15 to 30 per cent, being commonly noted before the appearance of 
secondaries (Konried). 

Secondary Stage. There is uniform agreement among very 
numerous observers that with the outbreak of secondary symptoms 
the red cells begin to fall rapidly, reaching in untreated cases as low 
as 2,000,000 or less (Konried). In ten cases Wilbouchewitch found 
an average decrease of 229,000 cells daily. At the same time the 
Hb continues to diminish and may fall to 55 or 25 per cent, within 
a few weeks or months. Riess denies that the Hb suffers particu- 
larly at the outbreak of the eruption. With the appearance of fever 
and new eruptions a further and more marked loss of red cells and Hb 
has been observed (Stoukovenkoff). Under favorable hygienic con- 
ditions and in feeble and especially in young subjects the anemia in 
this stage may be unusually severe. In untreated cases the disap- 
pearance of the eruption is not followed by any immediate improve- 
ment in the blood. 

Tertiary Stage. In untreated cases there can be no doubt that 
the anemia may progress until the pernicious type is established, but 
treatment usually limits the impoverishment of the blood, so that 
only moderate grades of anemia are commonly observed. Konried 
found an average of 4,000,000 red cells in ten cases, and from 50 to 
80 per cent, of Hb in twenty-two cases suffering from gummatous 
lesions. 

In several cases showing advanced tertiary lesions (gummata) at 
autopsy the writer has found different grades and types of secondary 
chlorotic and pernicious anemia. In one the spleen was much 
enlarged and contained gummata, while the blood showed the lesion 
of secondary pernicious anemia, with a tendency toward the micro- 
cytic type, and with low Hb-index. In other cases the abundant 
megalocytes with increased Hb closely resembled those of primary 
pernicious anemia. It is especially in infants that syphilis induces 
the grave types of anemia. 

Effects of Mercury upon the Blood in Syphilis. The effect of 
proper doses of mercury in arresting the progress of the anemia of 
syphilis was clearly stated by Wilbouchewitch, who reported an 
average gain of 102,000 cells daily in ten cases, while Keyes and 
many later observers have fully verified these results. That pro- 
longed use of mercury may of itself lead to marked anemia resem- 
bling that of syphilis was early noted by Becquerel and Rodier, and 
was also demonstrated both in man and animals by Wilbouchewitch, 
and later by Bieganski, Hayem, Lezius, Anc, Schlesinger, and 



340 THE ACUTE INFECTIOUS DISEASES. 

Jelleneff. The extent to which mercurial treatment may be carried 
without diminishing the red cells or Hb has been placed at twenty- 
four days, by Gaillard ; at twenty-five to thirty-five inunctions, by 
Konried ; at sixteen injections (grammes 0.5, 1 per cent. Hg-benzoate) 
by Jelleneff; and at 140 to 150 milligrammes of bichloride or 77 
milligrammes of benzoate, injected in increasing doses, by Lindstrom. 

During this period most observers agree that both red cells and 
Hb increase from the first, and many instances of moderate poly- 
cythemia are recorded. At the same time the eruption commonly 
disappears. If treatment is continued beyond this point, especially 
if the patient is salivated, the cells and Hb steadily and sometimes 
rapidly decline and well-marked mercurial anemia is established. 
Jawein, however, failed to observe any anemia during prolonged 
courses of inunctions. 

The Leucocytes in Syphilis. Leucocytosis was early observed 
in syphilis and its usual connection with the hyperplasia of lymph 
nodes was one of the facts that led Virchow to locate the origin of 
the lymphocytes in these structures. More detailed study of the 
behavior of the leucocytes was made by Wilbouchewitch, Bieganski, 
Jelleneff, Konried, and Rille, who have shown that the leucocytosis 
of syphilis is connected principally with the eruptions and the anemia 
of the disease. 

In the primary stage, before the appearance of the eruption, the 
leucocytes are usually normal (Kille), but Jelleneff found that an 
increase of white cells usually precedes the development of anemia, 
and Konried's cases showed a slight leucocytosis (maximum, 16,400) 
in the first weeks of the primary stage. 

In the secondary stage, with the appearance of eruptions, anemia, 
and hyperplasia of lymph nodes, the leucocytes are nearly always 
increased. In Konried's cases of untreated secondary syphilis the 
white cells were never under 10,000, while the maximum figure was 
17,500. Riess, however, found leucocytosis absent in many cases, 
but observed an increase to 20,000 in some instances, while the 
excess of lymphocytes was usually very distinct (maximum, 6S per 
cent.). The administration of mercury commonly reduces the white 
cells, which become normal with the disappearance of the eruption 
and the anemia. Jelleneff found the leucocytosis to be more nearly 
proportionate to the extent of the eruption than to the size of the 
lymph nodes, and noted leucocytosis in the absence of external signs 
of lymphoid hyperplasia. 

The increase affects principally the small and large lymphocytes, 
but the eosinophile cells may also be increased, especially in those 
cases with marked papular exanthems (Rille). Zappert found a 
slight increase of eosinophiles, 4.91 per cent., in one early case, but 
normal numbers in seven others. The proportion of lymphocytes 
diminishes as the patient improves, falling after each inunction 
(Eiess). In very severe cases there may be progressive polynuclear 
leucocytosis. Myelocytes have been found by Rille and others in 
both secondary and tertiary syphilis. 

In tertiary stages with gummatous lesions the leucocytosis usually 



SYPHILIS, TUBERCULOSIS, LEPROSY. 



341 



persists, bat lymphocytosis, though sometimes distinct, is less con- 
stant. Konried found 8500 to 17,710 leucocytes in nine cases. 

Justus' Test in the Blood of Syphilis. By a series of observa- 
tions in over 300 cases Justus came to the conclusion that in the 
blood of florid syphilis after injections of moderate doses of various 
preparations of mercury, or after inunctions, there is a period of a 
few hours or days during which the Hb is considerably reduced (10 
to 20 per cent.). After a certain period, varying with the general 
condition of the patient and the severity of the symptoms, the Hb 

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XII 






























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Course of changes in Hb in Justus' test. (Roman numerals indicate intravenous 
injections of sublimate.) 

begins to increase. In some cases the diminution continued only 
one day and in others it was repeated after each of three or four in- 
jections. The reaction was noted in all stages of the disease after 
the primary swelling of lymph nodes, and in hereditary syphilis, but 
could not be obtained " during or shortly before the symptoms of the 
disease begin to disappear.'' 

In the serum, within two minutes after the intravenous injection 
of bichloride, Justus found the spectrum of oxyhemoglobin. In 
blood smears immediately after the injection many pale degenerating 



342 THE ACUTE INFECTIOUS DISEASES. 

red cells were found, which disappeared within a few minutes. It 
thus appeared that the mercury had caused an immediate solution of 
red cells in the plasma. The specific gravity of the blood was not 
studied except in one case in wdiich it sho^\^ed irregular fluctuations. 

Justus' test has been applied in 121 cases, collected from the reports of 
Cabot, Jones, Christian and Foerster, Brown and Dale, Huger, Oppenheim and 
Lowenbach, and Tucker. In active syphilis it was positive in 46 cases, nega- 
tive in 15, and the Hb rose instead of falling in 13. In cases of chancre there 
are 11 positive and 20 negative results, and in chancroid 6 positive and 3 neg- 
ative tests. Three negative results with herpes. 2 positive results in genito- 
urinary tuberculosis, and 1 positive result in chlorosis and in sexual neuras- 
thenia complete the observations of the above writers. 

With only 62 per cent, of positive results in active syphilis, 30 
per cent, in chancre, and 67 per cent, in chancroid, it is evident that 
Justus' test can have only a limited value in the diagnosis of syphilis. 

Lately, however, Justus has reiterated his belief that the test is a 
specific sign of florid syphilis. He explains the negative resuUs of 
other observers as due to the use of too little mercury or the absence 
of lesions of the lymph nodes as a necessary sign of a florid stage of 
the disease. Only inimctions of ung. hydrarg. he now finds suitable 
for the test, and three grammes must be used with adults or one 
gramme with children. 

Further studies are required before the value of Justus' test can 
be shown, but on general grounds it would seem that the test would 
prove unreliable in many forms of anemia, when the globulicidal 
action of mercury might dissolve red cells. 

Congenital Syphilis. 

Syphilitic infants invariably suffer from anemia. In the mildest 
cases Loos found over 5,000,000 red cells and 65 to 75 per cent, of 
Hb. Schiff also found the usual polycythemia of infants in mild 
cases of congenital syphilis. In the majority of cases there is con- 
siderable loss of red cells and the Hb falls to a low figure, minimum 
21 per cent. (Loos). In the severer forms the blood may show the 
changes of secondary or progressive pernicious anemia, examples of 
which have been described by Loos, Luzet, Monti, Berggrun, and 
others. 

Whatever the grade of anemia, the changes are influenced by the 
special tendencies of infants' blood. Marked differences in the size 
of the cells are early established, nucleated red cells are frequently 
seen in abundance, and white cells, especially lymphocytes, are often 
present in greatly increased numbers. Loos noted an extreme degree 
of polychromasia in the large nucleated red cells in congenital syphilis. 
The leucocytes did not fall below 12,000 in any of Loos' sixteen 
cases, and in one fatal case rose to 58,000. Baginsky, and Monti 
and Berggrun have also reported excessive leucocytosis in similar 
cases, while the former author speaks of a distinct leukemic tendency 
to be found in the blood of congenital syphilis. 

The lymphocytes usually fall within normal limits for this age. 
Eosinophile cells are sometimes increased, especially when the eruption 



SYPHILIS, TUBERCULOSIS, LEPROSY. 343 

is extensive (Loos). The presence of a few myelocytes in the severe 
cases makes the resemblance of these cases of syphilitic anemia to 
V. Jaksch's anemia often very close, while the excess of large lympho- 
cytes may lead to confusion of the disease with lymphatic leukemia 
of Fraenkel's type. 

Congenital syphilis is recognized by Demelin as one of the common 
causes of melena neonatorum. In such a case, dying four days after 
birth from abdominal hemorrhage, the writer found in the blood the 
typical characters of idiopathic pernicious anemia, especially in the 
large nnmber of megaloblasts. The marrow was everywhere 
lymphoid, and showed pronounced megaloblastic changes. 

TUBERCULOSIS. 

The fact that the blood of consumptives may often fail to show 
any changes comparable with the pallor of the skin and the emacia- 
tion of these subjects was noted in the first studies of the blood by 
Andral and Gavarret, Becquerel and Rodier, and others. The dis- 
crepancy between blood and facial appearance was fully recognized 
by Laache, who, finding an average of 4,400,000 cells in fourteen 
cases, stated that phthisis of itself usually does not tend toward 
marked anemia. Similar results in the hands of Sorensen, Oppen- 
heimer, Gnezda, Barbacci, and Reinert, confirmed this opinion in a 
considerable group of cases, although well-marked chlorotic anemia 
was occasionally encountered. In the Massachusetts General Hos- 
pital series Cabot found forty-one out of sixty patients with more 
than 4,000,000 red cells, and sixty-nine of eighty cases with more 
than 50 per cent, of Hb. 

Yet Malassez had in 1874 reported well-marked anemia in some 
early cases, had seen the red cells fall over half a million in the 
course of one week, and found less than a million cells in an advanced 
case with diarrhea. 

In nearly all of their series of cases Laker and Fenoglio found low 
percentages of Hb, and the specific gravity was found markedly 
reduced by Schmaltz and Peiper. 

In 1893 current views were presented by v. Noorden, who stated 
that in pulmonary tuberculosis a loss of more than 20 per cent, of 
red cells or Hb is seldom observed unless from complications such as 
hemorrhage, suppuration, or amyloid degeneration. 

The subject was at this time thoroughly reviewed by Grawitz^ and 
Strauer, who found three distinct periods in the changes of the blood 
in phthisis : 

1. With beginning apical lesions, they generally found marked 
chlorotic anemia with loss of red cells, irregular leucocytosis, and 
reduction in dry residue and specific gravity. In robust subjects, 
however, the blood during this stage was sometimes normal. 

2. In pale, emaciated subjects with chronic phthisis and cavities, 
but without much fever, the blood commonly did not vary from the 
normal standard, the red cells numbering 5,000,000 or more, the 
leucocytes 5000 to 10,000, the dry residue of blood and serum being 



344 THE ACUTE INFECTIOUS DISEASES. 

moderately low, but the specific gravity higher than the dry residue 
would indicate. 

3. When hectic fever supervened, usually from suppuration in 
cavities, and the patient began to suffer from septicemia, the blood 
became rapidly impoverished, the red cells were then much reduced, 
the leucocytes frequently much increased, and the dry residue and 
specific gravity falling to a low point. 

The intense septicemia of rapidly advancing phthisis was found to 
yield some very severe grades of anemia, in one of which the red 
cells fell to 700,000. Similar cases have been reported by Malassez^ 
and Limbeck/ both of which suffered from marked diarrhea. In 
Limbeck's case there was also tuberculous peritonitis, and the blood 
showed marked poikilocytosis and increased Hb- index. 

In the attempt to correlate his own and Kobert's divergent results, Dehio 
described two different types of the disease, the marantic and the anemic cases. 
In the former group the patients showed a marked tendency to emaciate while 
their blood retained a good standard, while in the others all grades of chlorotic 
anemia might be observed. 

It would seem that the classifications of both Dehio and Grawitz 
are based on accurate clinical study. The following conclusions may 
be drawn regarding the general course of blood changes in tuber- 
culosis : 

1. The primary anemia of tuberculosis is seen not only in diseases 
of the lungs, but quite as frequently in chronic tuberculosis of other 
tissues, especially of the lymph nodes and bones, constituting the 
very numerous group of cases of " lymphatic anemia^ Moreover, it 
has recently been placed beyond doubt that the chronic anemia of 
Hodgkin's disease is in a large proportion of cases the result of tuber- 
culosis of lymph nodes. 

The peculiar character of these cases of secondary tuberculous 
anemia has been described by Laker, Neubert, Wiskeman, Vierordt, 
Bierfreund, Brown, Dane, and many others, and they constitute one 
of the largest groups of cases encountered in routine blood examina- 
tions. In appearance the patients clearly resemble cases of chlorosis 
and the blood shows a slightly or considerably reduced number of 
red cells, more marked loss of Hb, and usually slight relative or 
absolute lymphocytosis. Yet this description does not apply to all 
cases of early tuberculosis or phthisis, as some of them from the first 
appear anemic and yet show normal cells and Hb. 

2. The second group in which the blood is but slightly altered in 
quality, although cavities have formed in the lung and the patient is 
pale and emaciated, includes the majority of cases of chronic phthisis. 
One of the most striking examples seen by the writer occurred in a 
patient suffering from subacute tuberculous empyema from which the 
pus contained very large numbers of tubercle bacilli. But the same 
quality of blood is sometimes seen with early apical lesions and 
moderate emaciation, while considerable anemia may exist in moder- 
ately advanced cases of phthisis who are not suffering from distinct 
hectic fever. 



SYPHILIS, TUBERCULOSIS, LEPROSY. 345 

The cause of the concentration of the blood, or oligemia, in the 
average phthisical subject, for such must be the condition, is 
probably to be found, as indicated by Heidenhain, Gartner and 
Romer, and Grawitz,"^ in the specific lymphogogic action of the toxins 
of the tubercle bacillus, by which there is established a continuous 
excess in the balance of fluids which leave the tissues through the 
lymphatics. This view is strongly supported by the resemblance 
which exists between the tuberculous and the typhoidal processes, 
both showing a peculiar relation to lymphatic structures and both 
tending to concentrate the blood. Identical effects upon the blood 
follow also the experimental injection of tuberculin and typho- 
toxin. 

By this means the considerable destruction of blood which results 
from the chronic toxemia, hemorrhages, and malnutrition of the dis- 
ease is obscured, and only becomes visible at autopsies on these sub- 
jects when the shrunken appearance of the tissues finds a parallel in 
the diminished total volume of blood which is often apparent to the 
naked eye. In the majority of cases of well-advanced phthisis^ there- 
fore, approximately normal blood indicates considerable absolution of the 
toxins of the tubercle bacillus. Prolonged and profuse night-sweats, 
and sev^ere diarrhea, doubtless have a similar effect, which, however, 
is usually overbalanced by the destruction of blood which results 
from the associated toxemia. Normal blood is found in many 
phthisical patients who do not sweat or suffer from diarrhea. Yet in 
some extreme cases one or both of these factors may very well prove 
to be the chief influence in the concentration of the blood. 

3. The third group of cases includes those who are anemic from 
the first or who become anemic in the terminal stage of the disease, 
in either instance from the destruction of blood which occurs in all 
severe toxemias. Since the severe hectic fever of phthisis is largely 
referable to mixed infection, the condition established is not very 
different from the ordinary type of pyogenic sepsis. The destruction 
of cells may be quite rapid. Malassez observed losses of 730,000 
cells in one month, and 760,000 in three weeks in cases without 
hemorrhage. Here belong the acute cases with grave anemia described 
by Malassez, Limbeck, and Grawitz, from which it appears that the 
blood in tuberculosis may develop much the same characters as in 
pernicious anemia. Hills reports a chronic case of general tubercu- 
losis with melancholia, in which the red cells fell to 155,000. 

Morphological changes in the red cells are rather less marked than 
in most other types of secondary anemia, owing probably to the con- 
servative effect of a plasma of high gravity. When anemia exists it 
is usually of the simple chlorotic type with relatively high Hb-index. 
In his case of grave anemia Limbeck described extreme poikilocy- 
tosis, but nucleated red cells were apparently absent. In two very 
anemic acute cases lasting four and five weeks, the writer found under 
2,000,000 red cells, but there were no distinct megalocytes and no 
nucleated red cells. Cabot finds that nucleated red cells are usually 
absent in tuberculosis, even after hemorrhage, and contrasts this fact 
with their abundance in carcinoma. Degenerative changes in the red 



346 THE ACUTE INFECTIOUS DISEASES. 

cells in tuberculosis are not marked. In thirteen cases of uncompli- 
cated phthisis Grawitz^ found no signs of granular degeneration. 

Effects of Complications. Hemoptysis causes impoverishment of 
the blood in proportion to the extent of the hemorrhage. Malassez 
observed a reduction of 940,000 cells from small hemorrhages in a 
period of eight days. Amyloid degeneration is seen with advanced 
and anemic cases, but its effects on the blood have not been specially 
studied. Stenosis of the larynx and diabetes have been found with 
concentrated blood (Grawitz). 

Regeneration of the Blood in Phthisis. Prompt regeneration of 
the blood after hemoptyses has been observed by Malassez, but such 
improvement must depend largely upon the general condition of the 
patient. Laker came to the conclusion that if the Hb did not steadily 
improve after operation on tuberculous foci, it might safely be con- 
cluded that all of the disease had not been removed. In seven of 
Bierfreund's cases and in two of Brown's this rule held good, and 
three times a steady decline in Hb preceded for several weeks the 
development of symptoms of general tuberculosis [vide infra). 

In phthisis as loell as in other tuberculous processes great caution 
must be used in judging of the patienfs imp7T>vement from an increase 
in red cells or Hb. The writer has seen the Hb and red cells increase 
while the patient was rapidly losing flesh, the lesions advancing, and the 
total quantity of blood doubtless falling. In several of Bierfreund's 
cases the Hb steadily increased while the patient was developing general 
tuberculosis. 

The Leucocytes in Tuberculosis. In the majority of cases of 
uncomplicated tuberculosis the leucocytes remain within normal 
limits or are distinctly deficient in number. This rule has been 
established principally by later observers, since the earlier studies 
cited by Rieder, Reinert, and others indicated that tuberculous in- 
flammation usually excites leucocytosis. 

Yet Halla noted that leucocytosis was usually found only in 
advanced cases with fever, and Hieder distinguished the fresh cases 
from chronic febrile tuberculosis by the absence of any increase of 
white cells in the former. It is perhaps a still more uniform rule 
that leucocytosis is found almost exclusively in the febrile and anemic 
cases, but it is absent also in many febrile periods. 

In pulmonary tuberculosis an increase of leucocytes is usually 
referable to suppurating cavities, advancing pneumonia, severe anemia, 
or hemoptysis. Suppurating cavities^ when of recent formation, usually 
raise the leucocytes distinctly, 15,000 cells being frequently seen, and 
when the lung is softening the excess may be much greater. The 
leucocytosis usually persists while the fever continues. With old 
cavities the expectoration may be abundant, but the leucocytes usually 
fall to normal. 

In the pneumonia of various types which complicates phthisis the 
leucocytes are usually much increased, but considerable areas of 
diffuse tuberculous pneumonia may be found with acute miliary 
tuberculosis, which have failed to increase the leucocytes during life. 
A lobar pneumonia causes the usual leucocytosis, but the writer has 



SYPHILIS, TUBERCULOSIS, LEPROSY. 347 

seen both lungs consolidated and riddled with small cavities, in a 
case lasting five weeks, yet the leucocytes were never found above 
12,000. The absence of leucocytosis in these cases of acute phthisis 
which resemble pneumonia may often be of value in diagnosis. Simi- 
larly in a case of subacute empyema in which the tubercle bacillus 
was largely concerned, the leucocytes were found not to exceed 
14,000 during an acute febrile period. 

The leucocytosis of tuberculous cachexia is moderate, usually 
between 10,000 and 15,000. After hemoptysis the leucocytes are 
increased in proportion to the hemorrhage, but the increase is tran- 
sient. 

Acute general miliary tuberculosis offers the best illustration of 
the failure of pure tuberculous iniiammation to induce leucocytosis. 
Kieder, Limbeck, Warthin, and Cabot find rather a diminution of 
leucocytes, often to an extreme degree, and, as Warthin has shown, 
during a prolonged period. Minor suppurative complications seem 
to have no capacity to raise the Avhite cells, but in some reported 
cases a high percentage of polynuclear cells was noted among the 
scanty leucocytes (Warthin). 

Tui)erculous inflammations of serous membranes, when uncomplicated 
by pyogenic infection, follow the type of pure tuberculous inflamma- 
tion elsewhere and fail to increase the leucocytes. In many cases, 
however, there appears to be mixed infection, and the effusion, 
instead of remaining serous or serosanguinolent, becomes seropurulent 
and purulent. In such cases of pleurisy with seropurulent or puru- 
lent exudate the writer has found a moderate increase of leucocytes, 
usually in proportion to the height of the temperature. While it is 
undoubtedly true that the tubercle bacillus may of itself produce pus, 
the fact remains that it is seldom or never seen alone in purulent 
exudates. The slight leucocytosis that accompanies cases of purulent 
tuberculous inflammations of serous membranes is perhaps a further 
indication that these cases represent mixed infections. 

Tuberculous Meningitis. In the majority of reported cases of this 
important localization of the disease leucocytosis has been absent, as 
seen by Limbeck,^ Pick, Rieder, Sorensen. Yet in five of seven 
cases reported by Cabot and in one by Ziemke there was distinct 
leucocytosis, from 14,700 to 34,300, while in one of Rieder's cases 
there were 14,400 white cells. It is difficult to reconcile these con- 
flicting results. Some of the leucocytoses may have been ante-mortem 
phenomena, but not all. Ziemke's case was one of advanced general 
tuberculosis. The writer has seen cases with leucocytosis, but com- 
plicating terminal pneumonia was in each instance found at autopsy. 

Morphology of Leucocytes in Tuberculosis. In most cases of chronic 
tuberculosis, when the leucocytes are normal or diminished, the 
mononuclear cells are relatively in excess, but in some instances the 
usual rule is reversed, as in Warthin's case, and the polynuclear cells 
are in excess. Distinct lymphocytosis is seen in many chronic cases, 
especially those with large lymph nodes (lymphatic anemia). I^ymph- 
atic leukemia sometimes develops in tuberculous subjects, but the 
relation of the two diseases is uncertain. When distinct leucoovtosis 



348 THE ACUTE INFECTIOUS DISEASES. 

occurs, excess of polynuclear cells is usual, and pyogenic infections, 
etc., are indicated. 

Neusser believes that eosinophilia indicates relative immunity to tuberculo- 
sis. General experience seems to show that eosinophiles are frequently present, 
usually in normal numbers, in the blood in chronic tuberculosis, and some- 
times absent in the acute cases, or when there is fever and leucocytosis. 
Zappert found none in 2 of 5 cases of febrile tuberculosis. They are commonly 
increased, sometimes to an extreme degree, in the febrile period following in- 
jections of tuberculin. (Zappert.) 

Tuberculosis of Bones and Joints. Valuable studies in this field 
have been contributed by Brown in seventy-two and Dane in forty- 
one cases of tuberculosis of hip and spine. 

From these studies it appears that the above conditions are very 
frequently accompanied by moderate or marked leucocytosis (maxi- 
mum, 41,000), which is usually referable to secondary infection and 
the formation of pus. Yet Brown observed several cases with leuco- 
cytosis but without formation of abscess, and believes that leucocy- 
tosis may be referable alone to increased activity of the tuberculous 
process. A frequent cause of leucocytosis, often of marked degree^ 
was secondary infection of the sinus after operation. The leucocy- 
tosis was usually but not always associated with fever. Both authors 
agreed that when leucocytosis was absent in cases with abscess sec- 
ondary infection had not occurred, since the pus was sterile. They 
did not apparently consider the possibility that a micro-organism 
once present may disappear, or that leucocytosis may disappear when 
pus ceases to form. 

Myelocytes have been reported in scanty numbers in a few cases. 

Chemistry. Special chemical alterations of the blood in tubercu- 
losis have not been demonstrated, but the usual changes of secondary 
anemia have been reported in a few cases. Hammarschlag found a 
low gravity only in cachectic cases. Moderate reductions only were 
observed by Devoto and Scholkoff, but Schmaltz found a gravity of 
1.036 in an advanced case of phthisis, and Grawitz's case of grave 
anemia gave 1.032. 

The gravity is much lower, in proportion to the loss of cells, than 
in pernicious anemia. Dieballa found a density of 1.039 in a case 
of phthisis with 2,400,000 cells, and in one of pernicious anemia with 
only 840,000 cells. Mircoli found the serum actively hemolytic in 
the early stages of some cases. 

Freund found in the blood of tuberculous subjects a body which 
he regarded as cellulose, which Nischimura has likewise identified^ 
while others have found the same substance in tuberculous tissues. 
It is probably derived from the bodies of the tubercle bacilli. 

Bacteriological Examination of the Blood in Tuberculosis. 
Even before the discovery of the tubercle bacillus Weigert had 
pointed out the considerable involvement which the vessels may show 
in acute miliary tuberculosis. Weichselbaum, in 1884, was able 
with prolonged searching to find numbers of tubercle bacilli in stained 
specimens of the clotted blood of the great vessels in three cases of 
acute general tuberculosis. In the same year Meisels and Lustig 



SYPHILIS, TUBERCULOSIS, LEPROSY. 349 

both succeeded in finding tubercle bacilli in the blood intra vitam, 
the specimens having been squeezed from the finger-tip during a 
period of rising pyrexia. In the blood of the spleen the bacilli were 
much more numerous and ^Meisels recommended aspiration, of the 
spleen as an aid in the diagnosis of obscure cases. Rutimeyer also 
succeeded in finding many bacilli in the aspirated splenic blood of 
one of two cases examined shortly before death. In a case which 
eventually recovered Sticker, after considerable search, found a few 
bacilli in the finger blood taken on the tenth day of the illness. 

With the introduction of tuberculin, Liebman claimed to have found tubercle 
bacilli in 56 of 141 blood specimens, most abundantly about twenty-four hours 
after the injection of tuberculin. Grave doubt was, however, thrown upon all 
previous work in this field by the negative results obtained by Guttmann, and 
by Kossel, who called attention to the danger of contamination in such speci- 
mens. This method of diagnosis has not been followed up in later years, 
although Kronig, in 1894, recommended the staining of centrifuged laked 
blood in doubtful cases of miliary tuberculosis. 

In the blood of tuberculous cadavers various micro-organisms have 
been isolated by Pasquale, Petruschky, Canon, Welch and Nuttall, 
and others. Cultures of the blood during life have been made, by 
reliable methods, by Sittmann, Kraus, Kuhnau, Hewelke, White, 
Michaelis and Meyer, and Hirschlaff. 

Of their seventy-nine cases of advanced and usually febrile phthisis, 
there were twenty-three positive and fifty-six negative results. 
Staphylococcus pyogenes aureus or albus was isolated in twenty cases ; 
streptococcus pyogenes and a diplococcus in one case each, and the 
tubercle bacillus was once obtained from inoculation by Kuhnau. 
The pyogenic germs were sometimes found together. Jakowsky and 
Petruschky were rather more successful, drawing the blood through 
the skin, but this method is unreliable. 

There can be little doubt, therefore, that the blood in the late 
stages of phthisis suffers bacterial invasion as in other forms of septi- 
cemia. Kuhnau^s one positive result from twelve inoculations of the 
blood of severe febrile cases does not encourage further search for the 
tubercle bacillus in the blood of tuberculous subjects. Lasker also, 
in sixty-eight cases of hectic tuberculosis, found bacteria in the blood, 
streptococci but once. 

LEPROSY. 

Winiarski, in 1892, studied the blood in seventeen cases ilhistrat- 
ing various phases of this disease. In some cases he found polycy- 
themia, 6,380,000 to 6,090,000 red cells, which may perhaps be 
referred to local stasis, as the hands appeared cyanosed. Few of the 
patients showed any marked loss of cells, the average being 5,050,000 
for nine men, and 4,300,000 for eight women. Winiarski, there- 
fore, concluded that the milder cases of one or two years' standing do 
not suffer from any distinct anemia. Yet in two advanced cases with 
extensive lesions the red cells numbered 2,300,000 and 1,900,000, 
and the latter patient presented many signs of pernicious anemia. 



350 THE A CUTE INFECTIO US DISEASES. 

In these cases the anemia was referred to extensive ulceration. The 
Hb suffered ev^en less than the cells, usually registering 80 to 118 
per cent, in all but the two very anemic cases. The Hb-index was 
uniformly high, and in one case with 1,900,000 cells and 64 per 
cent. Hb the index reached 1.7. An increased diameter of the 
red cells was noted in this and other cases. The leucocytes were 
normal or subnormal in number, and the lymphocytes were in rela- 
tive excess (maximum, 47 per cent.), except when suppuration 
occurred. 

Brown, more recently, reported his observations in sixteen cases, 
eight of which appeared to be quiescent and presented normal blood, 
while only one showed severe anemia. He claimed to have found 
the bacillus in the leucocytes of the circulating blood in nine cases, 
eight of which showed the tubercular type of lesion. 

Streker also examined the blood of five " very anemic '^ cases of 
leprosy and found bacilli both free in the plasma and inclosed in 
leucocytes. The blood was drawn with antiseptic precautions from 
a deep incision through normal skin. These observations are quite 
in accord with the reports of Joseph regarding the large deposits of 
bacillus leprce in the spleen. 

Spronck claims that the serum of leprous subjects, in dilutions 
between 1 : 60 and 1 : 1000, agglutinates fresh living cultures of 
the bacillus of Hansen, and he recommends the use of this test in 
diagnosis. 

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Fischl. Zeit. f. Heilk., Bd. 13, p. 291. 



SYPHILIS, TUBERCULOSIS, LEPROSY. 35I 

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352 THE ACUTE INFECTIOUS DISEASES. 

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PART IV. 
CONSTITUTIONAL DISEASES. 



CHAPTER XVII. 

HEMORRHAGIC DISEASES, THE HEMORRHAGIC DIATHESIS, 
AND INTOXICATIONS. 

Hemoerhages of greater or less extent occur in many general 
diseases, in which the loss of blood is not referable to any specific 
predisposition on the part of the individual, but to peculiar condi- 
tions arising in the course of the disease. Such hemorrhages are 
regarded as symjotomatic. 

The chief causes of symptomatic hemorrhages are : 

1. Infections, as in any severe infectious diseases, such as septi- 
cemia, scarlatina, smallpox, measles, etc. 

2. Mechanical, as in partly asphyxiated infants, or other condi- 
tions of marked venous stasis. 

3. Toxic and autotoxic, as in poisoning by the so-called blood- 
poisons, or in jaundice, anemia, etc. 

4. Nervous, as in rare forms of hysteria. 

In the hemorrhagic diathesis probably all the above factors are at 
times unusually active, but there is believed to be in addition a 
specific, pre-existing, often hereditary change in the blood which 
largely determines the various manifestations of this diathesis. 
Modern bacteriological and chemical research has now considerably 
narrowed the scope of the hemorrhagic diathesis, and at present it is 
impossible to claim that any peculiar predisposition to hemorrhage 
exists except in cases of hemophilia. 

Yet it remains convenient to describe the various idiopathic pur- 
puras, scurvy, and hemophilia as closely related conditions. 

PURPURA HEMORRHAGICA. (WERLHOFF'S DISEASE.) 

The etiology of this disease still remains obscure, although the 
evidence points more and more toward some form of infection as the 
essential element in the majority of cases. The prominence of hemor- 
rhage in the symptoms of many infectious diseases has prepared the 
way for an acceptance of this view. In adults the extent of the 
hemorrhage attending well-identified forms of infection is rarely so 
great as in pronounced cases oi purpura Jiemo}')'ha(jica, in which often 



354 CONSTITUTIONAL DISEASES. 

no bacterial origin has been demonstrable. In infants^ however, 
infections by the ordinary pyogenic bacteria have become recognized 
as a frequent source of fatal hemorrhages constituting for that age the 
typical picture of Werlhoff ^s disease. 

There are now many cases of purpura hemorrhagica on record in which bacter- 
iological examination of the blood or viscera showed the presence of bacteria, 
which were regarded as the cause of the disease. In some cases bacilli were 
isolated, which were not fully identified. Letzerich's bacillus purjjurce in many 
respects resembled bacillus anthracis, and produced in animals, and possibly in 
the investigator's own person, a hemorrhagic disease resembling Werlhoff's. 
Streptococcus jnjogenes has been isolated in typical cases by Hanot and Luzet, 
Widal and Therese, Guarnieri, and others. In the first of these the disease 
was transmitted from mother to fetus, the latter dying and yielding a pure cul- 
ture from the blood. In infants, rapidly fatal hemorrhagic infections of this 
nature are not rare. 

Staphylococcus pyogenes aureus has been isolated by Lebreton, Litten, Fischl 
and Adler, Lewis, Silvestrini, and others. Fischl and Adler claim to have 
produced a fatal anemia in animals by inoculation with their coccus. Kolb 
obtained sterile cultures of the blood in five cases, but from the viscera of 
three of these, three to four hours after death, he isolated a diplobacillus 
which caused hemorrhagic septicemia in various animals. Auche obtained 
both the staphylococcus and streptococcus ia a fatal case, and Levi obtained 
in another both streptococcus pyogenes and the pneumococcus of Fraenkel. 

The pneumococcus lanceolatus was isolated postmortem by Claisse and by 
Claude. Bacillus pyocyaneus was obtained postmortem from a case of melena 
neonatorum by Neumann, and bacillus coli communis by Dansac, Legendre, and 
others. Hamilton and Yates report a rapidly fatal case showing, ten hours 
postmortem, bacillus aerogenes capsulatus. McLeod observed a case closely 
following Malta fever, and conditions described as purpura hemorrhagica 
have been reported as following pertussis, tuberculosis, congenital syphilis, 
etc. Negative results are reported in a fatal case by Denys ; in a purpuric 
complication of angina, by Legendre; and in chronic cases by Marfan, and by 
Millard. 

In the majority of the above cases the bacterium was obtained 
postmortem and from the viscera, or during life, from the lesions in 
the skin, and was rarely demonstrated in the circulating blood. 
Nevertheless, there can be but little doubt that a numerous group of 
cases of purpura hemorrhagica exists which is referable to a variety 
of bacteria, as represented in the above reports. 

It seems necessary, therefore, to provisionally separate the cases of 
purpm^a hemorrhagica of probable infectious origin from those which 
in no respect resemble an infectious disease, and are, therefore, 'probably 
acute manifestations of hemophilia. 

Changes in the Blood. In most of the febrile infectious cases 
of purpura hemorrhagica the anemia is not excessive and appears to 
be secondary to the infection and the loss of blood. In mild cases 
the red cells are slightly diminished in number, but exhibit no other 
alterations. Carriere and Gilbert report cases with 3,350,000 and 
3,900,000 red cells, many of which were microcytes. In more severe 
cases the red cells may be greatly diminished, in proportion to the 
extent of hemorrhage, but a microcytic type of red cell is usually 
prominent. The Hb-index is subnormal. Nucleated red cells occur 
when hemorrhages are large or frequent. 

In a fatal case in an infant, yielding a pure culture of streptococcus 
pyogenes at postmortem, the writer found the blood to show all the 



HEMORRHAGIC DISEASES AND INTOXICATIONS. 355 

characteristics of primary pernicious anemia. In four other cases of 
fatal hemorrhage in newborn infants at Sloane Maternity Hospital, 
the subjects had bled to death in the course of three to five days, 
but the blood showed only the characteristics of secondary anemia 
with leucocytosis. Leucocytosis has been noted by the majority of 
observers. In one case Carriere and Gilbert found 126,000 leuco- 
cytes, 90 per cent, polynuclear, and 5.8 per cent, eosinophile. In 
the writer's cases in infants the leucocytosis reached as high as 
56,000, but the eosinophiles were scanty. A very marked degree of 
polychromatophilia was observed in two cases by Spietschka. 

Hayem^ and Bensaude have described a peculiarity in the blood 
of purpura^ hemorrhagica which they claim to be pathognomonic. 
On allowing the blood to clot in a vessel it was found that after 
twenty-four hours the retraction of the coagulum is very feeble and 
fails to express the serum, as happens in normal blood. Associated 
with this feeble coagulation there is a marked reduction of blood 
plates (200,000 to 50,000). These two features of the blood were 
noted in sixteen cases oi picrpura hemorrhagiea, but in 152 examples 
of other diseases, some with purpura, the feeble clotting and loss of 
blood plates were never found to be combined. 

Non-infectious Idiopathic Purpura Hemorrhagica. 

In addition to the cases of purpura which arise in the course of 
infectious diseases or after various infectious processes, in which 
hemorrhage constitutes the chief symptom of a cryptogenic infection, 
there are other cases of rapidly fatal anemia attended with severe 
and repeated losses of blood for which a different etiology is indicated. 

Some of these cases are difficult to distinguish from pernicious 
anemia, but differ from that disease in the absence of megaloblastic 
changes in the blood or marrow, the great predominance of micro- 
cytes in the blood, and i\iQ prominence of hemorrhage among the 
symptoms. They differ from the infectious purpura in the more 
persistent hemorrhage, the absence of leucocytosis, and the absence of 
general symptoms of an infectious disease. 

Such cases have been reported by Ehrlich/ Engel, Muir, and 
others as pernicious anemia without characteristic changes in the 
blood or marrow. The writer can find no evidence on which to 
claim that pernicious anemia can exist without such changes in the 
marrow, and believes that these cases belong to the diseases referable 
to the hemorrhagic diathesis. This view is supported not only by the 
great dissimilarity in the blood changes of the two conditions, but 
by the absence of any marked deposits of iron in the viscera (Zaleskv). 
In Muir's case the marrow of the rib consisted almost entirely of fat 
tissue with very few normoblasts, while the sliafts of the bones were 
decidedly thicker than normal. Here the condition was apparently 
one of congenital agenesis of the marrow. The viscera contained 
considerable deposits of iron. 

Of the various etiological factors to which fatal purpura has boon 
attributed the non-infectious varietv niav be referred to tmv or all 



356 COXSTITUTIOXAL DISEASES. 

except the presence of bacteria. The underlying condition is probably 
identical with that of hemophilia of more typical course. 

Changes in the Blood. In the writer's case the clotting appeared 
to be abnormally rapid, as in the course of an hour the specimen in 
the hematocytometer diluted 1 : 100 with 0.6 per cent, salt solution 
became jelly-like. Grawitz has also noticed an increased coagula- 
bility of the blood in these cases after repeated hemorrhages. The 
red cells are rapidly diminished in number, reaching before death 
an extremely low figure. In a case of the writer persistent epis- 
taxis reduced them in three weeks to 456,000. In a. case reported 
by Billings they numbered 483,000. In Engel's case there were 
over 2,000^000. Contrary to the rule in secondary anemia following 
hemorrhage, nucleated red cells are extremely scarce or absent. The 
majority of the red cells are undersized and many are of oval shape. 
The leucocytes are normal or reduced in number, and of those remain- 
ing a large proportion (90 per cent., Engel ; 80 per cent., Ehrlich ; 
75 per cent., Billings) are lymphocytes. Eosinophile cells are scarce 
or absent. 

HEMOPHILIA. 

Hemophilia is an extremely hereditary constitutional anomaly 
which predisposes the subject to persistent and fatal hemorrhages of 
traumatic or spontaneous origin. The peculiar law of heredity which 
transmits the condition to males only through the female parents 
who are themselves usually exempt, as fully set forth by Grandidier 
and Stahel, not only marks this malady as the clearest possible illus- 
tration of the hereditary transmission of disease, but completely 
baffles the attempts to prove its dependence on any infectious agent. 

The essential lesion has been held by many to lie in an unnatural 
thinness and narroivness of the arteries (Virchow). In somewhat 
altered form this theory is maintained by Immerman and Oertel, 
who hold that there is a disproportion between the bulk of blood and 
the capacity of the blood system, referable in part to hypoplasia of 
vessels (Immerman) or to hydremic plethora. Proceeding on this 
theory Cohen claims to have considerably lessened the tendency to 
hemorrhages in a pronounced bleeder by a prolonged course of diure- 
sis and diaphoresis. In partial support of this mechanical theory 
are cited a few cases in which the heart was hypertrophied, and the 
vessels of small size, and showing fatty, hyaline, or granular degen- 
eration. 

A local origin is perhaps indicated by the case cited by Stengel, in 
which the hemorrhages were observed to occur from cuts above the 
neck, but never from those below. 

Recklinghausen holds that a disorder of the nervous system is the 
essential cause of the hemorrhages, and Henoch believes that the 
local condition is one of paralytic dilatation of vessels, followed by 
diapedesis. The condition has been seen in some very remarkable 
forms in neurotic and hysterical subjects (Stengel). 

Little success has followed numerous attempts to demonstrate 
essential changes in the blood. Albertoni claims to have found 



HEMORRHAGIC DISEASES AND INTOXICATIONS. 357 

diminished resistance in the red cells. The remarkable therapeutic 
influence of calcium chloride, described by Brunton, and reported by 
Wallis, supports the view that the chief alteration in the blood is in 
the content of salts. Wright finds that the bleeding in hemophilia 
is diminished by administration of calcium chloride, by inhalation 
of CO2, and by local application of the nucleo-albumin of the testicle, 
thyroid, and gastric mucosa. In morphology there is uniform agree- 
ment that the blood presents nothing peculiar. Decreased coagula- 
bility was held to be constant, by older writers (Grandidier, Lossen), 
and has later been observed by Schmidt and Manteuffel, who found 
that the blood in hemophilia requires longer than usual to clot, while 
its coagulation may be greatly hastened by adding a zymoplastic 
substance (fibrin ferment). Zavialoff claims to have found evidence 
that the red cells in hemophilia contain a cytoglobin, not present in 
normal blood, which prevents coagulation when liberated by the cells 
on shedding of the blood. The fibrin itself is apparently not greatly 
diminished, 5 per cent, having been found by Hey land ; 2.6 per 
cent., by Gavoy and Ritter, and 4.3 per cent, by Otto (cited by 
Litten). 

Studies in pathological anatomy have also failed to show any 
constant lesion of essential importance. In most of the viscera there 
are the lesions which follow acute or chronic anemia. Buhl described 
an unusually rich network of capillaries in the skin of one case, but 
the tissue was the seat of a chronic inflammatory process. Birch- 
Hirschfeld found normal vessels, slightly fatty heart muscle, and 
slight hyperplasia of the splenic stroma. Litten noted areas of 
granular degeneration in capillary endothelium, and irregularity in 
outline or widening of intercellular spaces between these cells, but 
suspected these changes to be artificial. In a series of cases hypo- 
plasia of the heart furnished the basis of Virchow^s theory. 

The blood changes are determined by the extent of the hemor- 
rhages, but leucocytosis has been absent in the few cases reported. 
In general, the blood resembles that of non- infectious purpura hemor- 
rhagica. 

SCURVY. 

Etiology. The most important fact in the etiology of scurvy is 
its intimate relation to improper diet. Aside from the almost exclu- 
sive occurrence of the disease in subjects whose food has been re- 
stricted in variety, it has been repeatedly demonstrated that the 
malady may be promptly cured by supplying some element previously 
deficient in the diet. Even a change in water supply has eradicated 
epidemics in garrisons. Scorbutic infants raj)idly recover from grave 
stages of the disease after such apparently trivial assistance as a 
change in the milk. Yet it has never been fully determined just 
what chemical substance is concerned in the causation and cure of 
the disease. It has even been claimed that diet has no relation to 
the malady, but all such reports have thus far, on investigation, 
failed to be supported, although they have demonstrated that the 



368 CONSTITUTIONAL DISEASES. 

dietetic error may be very trivial. Thus Seeland, regarding a some- 
what limited army ration as full mixed diet, came to regard the cases 
of scurvy under his care as of miasmatic origin. Accumulating 
evidence has shown that the most frequent source of the disease is a 
too exclusive diet of meat, especially if salted, and the absence of 
fresh vegetables, especially of potatoes, which are very rich in potas- 
sium. 

Guided by these observations various theories of origin of scurvy have been 
elaborated. Among these is the belief that the symptoms were caused by 
excess of NaCl in the blood, a condition long since shown to characterize most 
forms of anemia. That the essential element in the disease consists in a defi- 
ciency of potassium in the blood was held by Garrod, Liebig, and Hirsch.but 
a loss of potassium from the blood, with excess in the urine, while not constant 
in scurvy, is observed in other conditions. Ralfe and Cantani hold that a 
deficiency of salts of vegetable organic acids and corresponding diminution 
in the alkalinity of the blood is the important factor. Wright also maintains 
that scurvy is a form of acid intoxication arising from a diet rich in mineral 
acids and poor in bases. In seven advanced cases of scurvy from the beleaguered 
garrison of Ladysmith he found, by his alkalimetric method, that the blood 

/N N N\ 

was very deficient in alkalescence ( c7)_200 ^o^^^^l o^/" The administration 

of sodium lactate was very effectual in relieving the symptoms. 

To those who have observed the immediate effects of correction of 
diet in severe cases, especially in children, this field of investigation 
appears most likely to offer the true explanation of the disease. 

On the other hand, there are on record some very suggestive bac- 
teriological studies of scurvy, pointing toward an infectious nature of 
the disease. The injection into animals of blood from scorbutic 
patients caused purpuric lesions and internal hemorrhages in the 
experiments of Murri,^ Petrone, and others, Babes failed to find 
bacteria in the blood of a series of cases and failed to produce signifi- 
cant lesions by injecting blood into animals, but from excised portions 
of the spongy gums he isolated a bacillus, regarded as identical with 
one previously described by Miiller as common in the buccal cavity, 
and by injections of the comminuted tissue he produced, in two out 
of a series of rabbits, a form of hemorrhagic septicemia. From the 
visceral lesions he recovered this same bacillus along with the ordinary 
bacillus of hemorrhagic septicemia in rabbits. It does not appear 
that much significance can be attached to these results, although they 
are commonly quoted as strongly supporting the infectious theory of 
the origin of scurvy. Rosenell also recov^ered a somewhat similar 
bacillus from the viscera of a fatal case of scurvy, but inoculations 
into rabbits were negative. Entirely negative results were obtained 
by Wieruschky in a large number of cases. Most of his cultures of 
the blood were sterile, but in fourteen cases he found various germs 
to which he could not assign any relation to the disease. 

In recent years the bacteriological study of scurvy has not proved 
an inviting or accessible field to competent bacteriologists. 

A recent important study directed toward the chemistry of the blood and 
of digestion is that of Albertoni, who has shown that there is a marked loss 
or complete absence of free HCl in the gastric juice in scorbutic patients, 



HEMOBRHAGIC DISEASES AND INTOXICATIONS. 359 

that gastric digestion is deficient, that intestinal putrefaction is excessive, and 
that there are abundant evidences in the urine of absorption of toxic prod- 
ucts, while the absorption of fats and carbohydrates is deficient. In the 
blood Albertoni found a much greater reduction in iron (0.3 to 0.39 per cent.) 
than is seen in other anemias with equal numbers of red cells. The sodium 
and potassium varied between normal limits. The greenish-yellow color of 
the serum and the excess of pigments in the urine were evidences of active 
destruction of blood cells. 

Changes in the Blood. The morphological changes in the blood 
in scarv^y resemble those of secondary anemia from hemorrhage. 

The red cells in cases of average severity nnmber between 3,000,000 
and 4,000,000, but with severe hemorrhages the anemia may be- 
come very grave, as in Bouchut's case, in which, after three weeks 
of persistent epistaxis, the red cells were reduced to 557,000. The 
reports of Uskow, Hayem,^ Wieruschky, and Albertoni show that 
the red cells vary in number and size according to the length and 
severity of the disease. Litten saw many megalocytes and shrunken 
microcytes, evidently in severe cases. Albertoni found evidences of 
solution of red cells in the plasma, and an excessive number of pale 
cells or fragments of cells have been described by several observers. 
The Hb-index is low, White finding 20 per cent. Hb with 40 per 
cent, of red cells, while Becquerel and Albertoni found the iron- 
content much lower than in other anemias. Opitz and Duchek, 
however, reported a normal or increased proportion of iron. 

The proportions of sodium and potassium salts vary as in other 
anemias, and the claims of Ralfe and Cantani that the alkalinity of 
the blood is deficient have not been supported. 

On account of the frequency of inflammatory complications and 
hemorrhages the leucocytes are usually increased, Uskow finding 
as high as 47,000. Litten, however, observed no leucocytosis, and 
the writer, in two well-marked but uncomplicated cases, found no 
increase. 

In Barlow's disease, which is a form of scurvy with extensive 
subperiosteal hemorrhages, the condition of the blood varies greatly, 
according to the general condition of the patient and the number and 
extent of the hemorrhages. All grades of post-hemorrhagic anemia 
have been observed, up to Reinert's fatal case, in which the Hb fell 
to 17 per cent, and the red cells to 976,000. The disease is often 
associated with rachitis. 



HEMOCYTOLYSIS. 

When the isotonic tension of the plsma falls below that of the red 
cells, the Hb may become dissolved in the circulating blood, and the 
shadow-like remnants of the stroma of the cells are distributed in 
the plasma. In other conditions, even without loAvered isotonic ten- 
sion of the plasma, the red cells may be split up into fragments. 
The purest examples of the former variety of destruction of red cells 
are perhaps seen after extensive infusions of salt solution, Avhile the 
latter variety is observed especially from the effects of certain blood 



360 CONSTITUTIONAL DISEASES. 

poisons — e. g., potassium chlorate. Usually the two processes are 
combined, as in the anemias and infectious diseases, while in some 
conditions the exact manner of the solution of Hb remains unex- 
plained. 

The chemical processes in the cell leading to the solution of Hb 
are somewhat obscure, since this constituent is probably held in 
chemical combination with the stroma and not merely held in situ by 
a hypothetical cell membrane. Thus the most extreme form of 
hemoglobinemia (paroxysmal) may occur in blood of comparatively 
high isotonic tension, while the high grades of globulicidal activity 
of the plasma in infectious diseases are not always associated with 
hydremia. Hemocytolysis is followed by diminution in the alkal- 
escence of the blood owing to the discharge of phosphoric and 
glycerophosphoric acids into the plasma during the passage of Hb 
into solution (Kobert). 

The studies that have followed the work of Bordet and Ehrlich on hemolysis 
have elucidated the conditions governing this obscure process while leaving 
its true nature unexplained. It has been shown that the serum of one animal 
possesses, as a rule, power to dissolve the red cells of heterologous species. 
This result depends upon the interaction of two agents, one of which, the 
'' immune body '' (amboceptor), is specific for each species of animal ; while the 
other, the complement (alexin), may be furnished by the animal whose blood 
cells are dissolved. The immune body resists heating to 55° C, which usually 
destroys the alexin. 

When washed blood cells are treated with hemolytic serum heated to 55° C. 
(alexin destroyed), hemolysis fails until fresh unheated serum is added. 
Different immune bodies are developed in the process of immunization against 
different heterologous bloods, and Ehrlich claims that there is a similar multi- 
plicity of alexins. In any event he believes that the interaction of these 
various agents is of the nature of a chemical union, each of the bodies being 
consumed in the process, while the subsequent changes in the cell are of a 
digestive nature, as by ferments. This view has been actively combated. 

Buchner and Gruber believe that the alexin unites directly with the red 
cells without the intervention of an amboceptor. Baumgarten argues that 
hemolysis always results principally from the changes in isotonic tension. In 
hemolytic serum the same changes in the red cells occur as in hypisotonic salt 
solution, viz., shrinkage and discharge of Hb in droplets. Baumgarten finds 
also that when foreign red cells in 4 per cent, salt solution are added to inac- 
tivated specific sera (alexin destroyed by heat) hemolysis begins at once. 
Here the alexin appears to be nothing more than salt. He also claims that 
abrin and ricin dissolve red cells only in hypisotonic solutions. 

The morphological changes occurring in dissolving red cells are 
also not fully identified, although it appears more and more probable 
that many forms of degeneration previously described in red cells are 
the precursors of the complete solution of Hb. The polychromatic 
degeneration of Maragliano, that of Gabritschewsky, and the granu- 
lar degeneration of Grawitz are probably morphological signs indi- 
cating approaching or progressive solution of the cell. Fukuhara 
has described the morphological changes in blood cells treated 
with hemolytic sera, hypisotonic salt solution, and 2 per cent, 
soda solution. The changes induced were in each case similar, 
except that the sera agglutinated the cells. The cells became sw^ollen 
and dissolved with slight tendency to disintegrate, or they became 



PLATE XIII, 



Fig. 1. 




^^"l^^^P 



^"^tnat 



Fig. 2. 




Agglutinated Red Cells. 

Fig. 1. Stained agglutinated human red cells from a specimen prepared^ in the test tiibe. 

Fig. 2. Effect of a drop of hemolytic serum added to a dried smear of human red cells. 

Photographed by Dr. B. H. Buxton. 



HEMORRHAGIC DISEASES AND INTOXICATIONS. 361 

crenated and the protoplasm broke up into granules or discharged 
blood plates, which subsequently dissolved (Plate XIII.). 

From extensive study of the anemia following pyrodin poisoning 
Tallqiiist concludes that the -presence of mia^ocytes is a sign of hema- 
tolysis, while megalocytes indicate regeneration of the blood. The dis- 
solved Hb imparts to the plasma, in the eosin-stained specimen, an 
abnormal reddish tinge, and discolors the serum. When present in 
moderate amount it may be gradually transformed by the liver into 
bile-pigment, which is occasionally reabsorbed from the biliary 
passages, causing hematogenous jaundice. The presence of an exces- 
sive amount of Hb in the plasma is apparently the chief reason why 
it is sometimes excreted by the kidneys and appears in the urine as 
hemoglobin or methemoglobin. During its passage through the liver, 
kidney, and other tissues a considerable portion of the iron is retained 
in the granular or diffuse form of hemosiderin. 

Under some conditions not fully understood, but believed by 
Thoma to consist essentially in the relative absence of oxygen, dis- 
integrating red cells are transformed largely into brownish granules 
or crystals of hematoidin. This change usually takes place without 
the intervention of cellular activity (Thoma). It frequently occurs 
postmortem. 

Broken fragments of red cells and the stroma of disintegrated cor- 
puscles float in the plasma for a time and may be observed in the 
stained specimen, but are gradually englobed by phagocytic cells and 
lodged in various organs, principally in the spleen. 

Hemolysis of Infectious and Toxic Diseases. The anemia of 
the infectious diseases, especially in grave septic conditions, is estab- 
lished rapidly and to a large extent through the direct solution of red 
cells by the globulicidal plasma. The condition is often attended 
during life by hemoglobinuria, and after death extensive deposits of 
blood pigment are found in all viscera, especially in the spleen and 
liver. 

The degree and character of the hemolysis of some infectious dis- 
eases have been studied in detail by many observers, and the active 
principles of many bacteria have been isolated and tested, as tetano- 
lysin (Madsen) ; pyocyanolysin (Bulloch, Lubenau) ; staphylolysin 
(Neisser, Wechsberg) ; typholysin (Levy). 

Isolysis. Several observers, including Ascoli, Kraus and Clair- 
mont, and Halpern have studied the agglutinating and solvent action 
on human red cells of the sera of human subjects. This action of 
so-called normal human blood upon red cells of other human subjects 
is spoken of as isolysis and the active agents isolysins. Ascoli found 
in the serum of seventeen healthy subjects varying degrees of agglu- 
tination and solution of the red cells of other subjects, but not in 
dilutions greater than 1 : 20. Kraus and Clairmont found one 
active serum in ten healthy subjects, and Donath four in twelve 
subjects. 

AH observers agree that the isolysins are probably developed from 
the absorption of disintegrating red cells or from the absorption of 
bacterial products. Ascoli found the red cells of anemic subjects 



362 CONSTITUTIONAL DISEASES. 

very susceptible to many normal sera, but secured no effects from 
the sera of several cases each of chlorosis, abscess, acute rheumatism, 
pleurisy, plumbism, nephritis, anchylostomiasis. Actively hemolytic 
sera were obtained from cases of pneumonia, tuberculosis, cancer, 
malaria, and typhoid fever, but not in every case. 

Kraus and Clairmont, in 150 cases, found many active sera, espe- 
cially in scarlatina, typhoid fever, pneumonia, and tuberculosis. The 
effects of such sera are, of course, referable to bacterial products and 
disordered metabolism, but there appears to be only a difference of 
degree between their action and that of the isolysins in apparently 
healthy subjects. 

The presence of agents dissolving leacocytes, ^^ leucocidins," has 
been demonstrated in the blood in some infectious diseases, and they 
may be developed by injections of these cells from one animal into 
another. Van de Velde, and Neisser and Wechsberg find that the 
leucocidins develop strongly in cultures of staphylococcus pyogenes 
aureus on the fourth day. That they are not identical substances 
with the hemolysins is indicated by the facts that they appear in the 
cultures at different times, while the addition of living leucocytes to 
the cultures neutralizes the leucocidin, but has little or no effect upon 
the hemolysin. 

In malaria various forms of destruction of red cells occur, which 
will be considered later. 

The possible therapeutic use of hemolytic serum has been studied by Can- 
tacuzene. He found that 15 c.c. of a hemolytic serum killed rabbits in one to 
two minutes, with spasms and cyanosis. Much smaller doses diminished the 
red cells in forty-eight hours to 300,000, Hb 35 per cent., and gave marked 
leucocytosis. One-tenth to one-thirtieth c.c. increased the red cells to 
8,800,000, but after eight days they fell to normal. Repeated minimal doses 
raised the red cells to 9,000,000, Hb 110 per cent., and caused leucocytosis. 

Bielonovsky reports equally good results in man. 

Special Conditions in which Blood Cells are Rapidly- 
Destroyed. 

Burns. The stady of the pathology of the blood in burns appears 
to have begun with the observations of Baraduc, 1862, who attributed 
the numerous thromboses to thickening of the blood from exudation 
and venous stasis. In 1865 Schultze noted the crenation and minute 
subdivision of red cells exposed to 52° C. This process can be 
readily followed in a fresh specimen heated over a flame. 

The experimental study of the tissue changes in burns, thus began, 
led Wertheim, v. Lesser, Silberman, Welti, Demme, Pawlowsky, 
Tappeiner, Markusfeld and Steinhaus, and others to conclude that 
death from burns is referable to destruction of blood cells with throm- 
boses, and to concentration of the blood from exudation and stasis, 
while some of the authors lay much stress on the toxic effects 
observed in the kidneys or other viscera. 

The changes observed in the red cells were extreme in degree, but 
not always extensive. The cells were distorted, subdivided, broken 
up into globules or granules, many " shadows '^ remained, the Hb 



HE3I0RRHAGIC DISEASES AND INTOXICATIONS. 363 

often gathered in circumscribed masses in the cell, and basic staining 
granules or areas appeared in the cells. 

On the other hand, Hoppe-Seyler and many later observers could 
not find sufficient changes in the red cells to account for death, and 
they favor the belief that death is due to a toxic substance developed 
in the blood and tissues. Fraenkel, from a study of seven cases at 
autopsy^ concluded that death could be explained only as the result 
of toxemia. Schjerning and others thought the poison must be the 
potassium salts set free from the red cells. Kajanitzin isolated from 
the blood of burned animals a poisonous ptomain belonging to the 
group of cadaveric muscarins. Keiss extracted from the urine 
poisonous bodies resembling pyridin. 

The results of neither of these studies, however, have enjoyed full 
verification, and Pawlowsky rejected the toxic theory after finding 
that aseptic treatment of the blood and viscera of burned animals 
left them non-toxic. 

Bardeen, from the histological study of five cases, concludes that 
toxemia must exist to account for the degenerations of the tissues, and 
especially the focal necroses in the lymph nodes and liver. 

Hemoglobinemia and hemoglobinuria have been described by 
Hoppe-Seyler, Tappeiner, and others. Locke has contributed the 
only detailed study of the numerical changes in the blood cells. He 
found that an immediate increase of 1,000,000 to 2,000,000 red cells 
occurs in severe cases, and 2,000,000 to 4,000,000 in fatal cases, 
while the blood is thick and dark purple in color. A rapidly rising 
leucocytosis occurs in all cases, reaching 30,000 to 40,000 in recover- 
ing cases, and usually more than 50,000 in fatal ones. 

The percentage of polynuclear cells is not greatly increased (60 to 
87 per cent.). He found slight morphological changes in the red 
cells. 

Snake Poison. The fatal effects of the bites of many snakes is 
largely referable to very active agglutination and solution of red 
blood cells by the proteid constituents of the venom, as demonstrated 
by Mitchell. A serum capable of inhibiting the action of the poison 
has been prepared by Sewall, Calmette, and Frazer. It has recently 
been shown by Flexner and Noguchi that snake venom is inert upon 
washed blood cells, and hence that it contains no complement, but only 
amboceptor, and that it destroys bactericidal properties of blood 
serum through action on the complement of the serum. 

Auche and Vaillant observed rapid solution of the red cells in 
proportion to the quantity of snake poison injected by bite or svrino-e. 
They found reductions of 1,500,000 to 2,000,000 cells iii short 
periods. In surviving animals many nucleated red cells appeared. 
Polynuclear leucocytosis developed in severe cases, both fatal and 
favorable, in one-half to two hours, lasting three to four days or 
until death. 

Arsenic. Vryens finds that hemoglobinemia occurs rarely in 
acute poisoning by arsenious acid and no destruction of red cells fol- 
lows doses less than 0.01 gm. per kilo of body weight (9.6 gm. for 
140 pounds). Stockman and Greig found no chano-es in the red cells 



364 CONSTITUTIONAL DISEASES. 

from toxic or fatal doses in rabbits. Muir observed thirty-one cases of 
chronic arsenical poisoning in which the red cells averaged 4,947,000, 
Hb 92 per cent. The marrow showed distinct increase of normo- 
blasts. Mann and Clegg report 2,700,000 and 1,800,000 red cells 
in chronic cases, and they say that anemia may be very severe in 
cases which recover. 

Fumes of arseniuretted hydrogen are very active, when inhaled, 
in dissolving red cells, producing hemoglobinemia, hemoglobinuria, 
with Hb-infarcts in the kidneys, and acute degeneration of the 
viscera. 

Poisoning by toadstools, by the alkaloids of quillaia saponaria 
(saponin, sapotoxin), of solanum, and other motor depressants, dis- 
solves red cells in the blood and leads to hemoglobinuria (Kobert). 

In a fatal case of poisoning by guaiacol, Wyss observed rapid 
destruction of red cells, finding many degenerated, fragmented, 
shrunken red cells and megalocytes on the second to third days. 
The white cells were considerably increased and the majority of these 
were lymphocytes. 

Transfusion of Salt Solution, Serum, and Defibrinated Blood. 
Siegel and Schram both found no improvement in the regeneration of 
the blood from the transfusion of salt solution or of serum in animals 
after bleeding, and while it has since been shown that the regenera- 
tion is somewhat more rapid and complete after salt infusion, yet this 
procedure must be regarded as of more value as a means of saving 
life than as a stimulant to blood formation. The direct effects on the 
blood of infusion of defibrinated blood seem to be much more favor- 
able. On the other hand, after the transfusion of blood, the above 
observers, and others, have found a rapid increase in the number of 
cells, and Bizzozero reported the same effect after transfusion of 
defibrinated blood in animals. Quincke was one of the first to note 
an increase in red cells in pernicious anemia as a result of transfusion 
of blood, and similar observations have been made by Ziemann in 
anemia and scurvy. It would seem, from the observations of Biz- 
zozero and of Bareggi that the red cells are quite resistant to the 
process of defibrination and injection. Of the immediate effects of 
salt infusion upon the blood of the human subject there are a few 
reports at hand which indicate that it has considerable influence in 
lowering the number of red cells and increasing the leucocytes. 

Methemoglobinemia. Various poisons not only dissolve red 
cells, but at once transform the hemoglobin into methemoglobin. 
The blood in such cases may exhibit a distinct chocolate color. 

Potassium chlorate is one of the most frequent forms of poisoning 
which cause destruction of red cells with methemoglobinemia. 
According to v. Mering the KCIO3 acts directly upon the cells and 
is itself thereby reduced, while Marchand, Falck, and others hold 
that the serum is first altered. Brandenburg reports a fatal case in 
which the red cells fell in six days from 4,300,000 to 1,600,000. 
Many of them were deformed. The blood and serum were chocolate- 
colored and gave, during the first five days only, the spectrum of 
methemoglobin. There was marked leucocytosis (20,000). 



HEMORRHAGIC DISEASES AND INTOXICATIONS. 



365 



In a case fatal in six days Jacob noted progressive pallor of the 
red cells, numerous rouleaux of ^^ shadows/' little or no red -cell 
detritus, and numerous poikilocytes and megalocytes. The cells 
increased from 1,800,000 to 2,200,000 before death. 

There was continuous leucocytosis, reaching 80,000, while the 
nuclei of the white cells were very pale and the neutrophile cells 
were deficient in granules. In a case which recovered Markwedel 
observed all the above changes, and while the leucocytosis subsided 
on the fourth day some red-cell shadows persisted for two weeks. 

Sticker reports a severe case of poisoning after a vaginal douche 
by solution of chromic acid, the patient passing brownish urine. He 
refers to other fatal cases with similar signs. 

Nitrites. Poisoning by nitroglycerin and by amyl nitrite is said 
to occur in the manufacture of these chemicals, and to be followed 
by methemoglobinemia. 

Nitrobenzol poisoning was studied in a fatal case by K. Ehrlich 
and Linden thai. 

Fig. 36. 





9/1 



Acute degeneration of red cells. Nitrobenzol poisoning. Subdivision of cells and appearance 
of basophilic granules in them. (K. Ehrlich, Lindenthal.) 



Ten hours after the initial symptoms the blood was chocolate-colored, the 
serum brownish, and spectral analysis showed the presence of methemoglobin, 
which disappeared by the eighth day. The red cells were rapidly reduced, 
2,275,000 on the fifth day, and falling to 900,000 before death on the 
nineteenth day. Poikilocytosis appeared on the third day and soon 
reached a remarkable degree. Polychromatic and fragmented cells were 
abundant. Nucleated red cells were first seen on the third day, and there- 
after in very large numbers and of all sizes. On the ninth day the leu- 
cocytes, previously low, rose suddenly to 61,000, and the nucleated red cells 
were reported at 24,700. Judging from the authors 
difficult to distinguish between karyorrhexis in some 
treme forms of the granular degeneration of Grawitz. 
40 per cent., which, with 900,000 cells, was a remarkably high PIb-index. 
There were many myelocytes among the white cells, so that at one time the 
blood presented the appearance of leukemia. The bone-marrow was not 
examined. These interesting observations recall the etlbrts of Biiiuami and 



plates it was. perhaps, 

nucleated cells and ex- 

The lib fell steadilvto 



366 CONSTITUTIONAL DISEASES. 

Dionisi to produce experimental pernicious anemia by means of toluendiamin. 
The morphological characters of the blood described by Ehrlich and Linden- 
thai probably represent an extreme degree of the effects upon the blood of the 
entire group of anilin poisons. 

Mohr observed six cases of benzol poisoning among workers in benzol fac- 
tories. In all there was methemoglobinemia, schistocytosis, and hemoglo- 
binemic degeneration, while nucleated red cells, microcytes, and macrocytes 
were numerous. 

Pyrogallol and pyrogallic acid have caused death with symptoms of 
methemoglobinemia (Grawitz). 

Antifebrin has been found to produce extreme methemoglobinemia 
in animals (Lepine) and in man (Miiller), but neither of these 
observers could find any morphological changes in the blood of sub- 
jects dying from this cause. 

Brown describes a case fatal in eight days after taking sixty grains 
of acetanilid. There was progressive anemia from destruction of 
blood, the red cells falling to 1,100,000, Hb 30 per cent,, while of 
25,000 nucleated red cells 20 to 40 per cent, were megaloblasts. 
The leucocytes rose to 66,450 with proportions normal. The alka- 
linity was said to be greatly reduced and there was hematoporphy- 
rinuria. 

Antipyrin produces toxic symptoms similar to those of antifebrin, 
but reports on the examination of the blood in severe cases are want- 
ing (see Falk, Miiller). 

Toluendiamin poisoning was studied experimentally by Schwalbe 
and Solley, who found that it produced granular degeneration of the 
red cells with extrusion of blood plates. 

Poisoning by CO. A bright cherry-red color of the blood is a 
characteristic sign in cases of ^' gas poisoning,'^ and is referable to 
the presence of CO-Hb. The methods of diagnosis of this condition 
by spectral analysis have already been considered. 

Poisoning by Hydrocyanic Acid. The bright red color of the blood 
in this condition is referable to the presence of cyan-methemoglobin 
(Kobert), which gives a characteristic spectrum. The manner 
of death is believed by Geppert to be through inhibition of the 
metabolic processes in tissues, so that CO2 is not discharged and 
oxygen not absorbed. Morphological changes in the blood have 
not been reported. 

Paroxysmal Hemoglobinuria. This remarkable condition, con- 
sisting essentially in the rapid solution in the blood stream of enor- 
mous numbers of red cells, followed by the appearance of Hb in the 
urine, was recognized by Stevv^art more than a century ago (1794), 
and has been widely studied in its various phases ever since* 
Chvostek^s monograph reviews the literature up to 1894. 

Etiology. The most peculiar feature of this malady is the appar- 
ently trivial nature of the exciting causes of solution of the red cells. 
Slight exposure to cold, even of a part of the body, has been the 
most common exciting cause, many confirmed subjects being able to 
induce an attack at Avill. Other exciting conditions have consisted 
in mental excitement or nervous irritation, and muscular or nervous 
exhaustion. 



HEMOBEHAQIC DISEASES AND INTOXICATIONS. 367 

In recently malarious subjects Tomasselli and Koch have placed 
beyond doubt that quinine is a frequent exciting agent. An infec- 
tious origin has been suggested by Layral and by Cima. The 
underlying conditions which predispose to the disease are known to 
include only constitutional syphilis (Boas, Gotze) and malaria (Legg), 
but in a considerable proportion of cases neither of these factors 
appears to exist. 

Pathogenesis. That a vasomotor neurosis is prominently concerned 
in the solution of blood cells is strongly suggested by the frequency 
with which nervous influences have been known to precipitate the 
attack. This theory, first suggested by Dapper in 1868, has been 
uniformly maintained up to the present time by the majority of 
observers. The further attempt to explain the destruction of blood 
by this means has as yet been unsuccessful. Chvostek concluded 
that as a result of malaria, syphilis, etc., the red cells possess dimin- 
ished resistance, not to cold, but to mechanical traumatism, and that 
when the circulation is disturbed by vasomotor contraction of periph- 
eral vessels the fragile red cells become dissolved. He supported 
his view by showing, as Dapper had done, that the disturbance of 
circulation following ligation of a finger may cause solution of red 
cells in the absence of cold. With Pavy, McKenzie, Rosenbach, and 
others, he attributed to the kidney a special importance in the process. 
Murri^ has offered evidence to show that the red cells are abnormally 
susceptible to the effects of cold, and that by paralytic dilatation 
of peripheral vessels they become exposed to cold and dissolved. 
But Rodet failed to find by experiment any lack of resistance of the 
red cells against cold, and numerous cases have been observed to 
follow muscular and mental overexertion (Fleischer, Strobing). 
Ehrlich supposes that in the predisposed subjects exposure to cold 
causes the development of ^' ferments '^ which dissolve the red cells. 

Postmalarial Hemoglobinemia. The relation of blackwater fever 
to malaria has been the subject of much discussion, the opposing 
views in which are fully presented in the studies of Koch and of 
Plehn. From the observations, correlated and largely contributed 
by these observers, it is evident that hemoglobinuria arises : 

1. As a direct result of the action of the malarial parasite upon 
the blood. 

2. As an immediate effect of the administration of quinine on 
patients predisposed to hemoglobinemia from present or pre-existing 
malarial infection. 

3. It is probable that hemoglobinuria results from simple exposure 
to cold, or to other exciting agents, in subjects who have acquired 
the predisposition through previous malarial infection. 

Plehn fully demonstrates that blackwater fever may occur in 
patients suffering from malaria, without the administration of 
quinine, and with or without notable exposure to any of the ordinary 
exciting causes of the condition. Numerous cases collected or 
observed by Plehn leave this fact apparently beyond doubt. 

Plehn's report that a special variety of parasite is concerued in 
blackwater fever has not been confirmed, and it is probable that the 



368 CONSTITUTIONAL DISEASES. 

author mistook the peculiar appearance of granular uegeueration of 
red cells for minute parasites. The most extensis'e changes of this 
type observed by the writer were seen in severe malarial cachexia at 
Montauk^ 1898, and in many instances the altered red cells presented 
a remarkable resemblance to corpuscles infected with young malarial 
parasites. 

On the other hand, Koch has recently drawn contrary conclusions 
from a thorough study of forty-one cases. He finds that hemoglo- 
binuria does not necessarily follow even when 80 per cent, of the red 
cells are infected with parasites. The great majority of his cases 
developed a few hours after the administration of quinine. With 
regard to the relation of malaria to black water fever he found that : 

(1) Parasites may be present in the blood, but there is no relation 
between their numbers and the severity of the hemoglobinuria. 

(2) The patient may have suffered from malaria some weeks or 
months previously. (3) In two fatal cases in the tropics he found 
neither parasites in the blood nor pigment in the viscera. 

Koch concludes that life in the tropics, and especially malarial 
infection, predispose certain individuals to hemoglobinuria, but that 
the attack is invariably excited by quinine, or occasionally by ex- 
posure to cold or heat, etc. His further claim that no cases are 
referable to malaria alone cannot be accepted in the face of the obser- 
vations of Plelin and many others, of fatalities occurring in the course 
of malarial infections which have not been treated by quinine. 

Changes in the Blood. The destruction of red cells very 
promptly reduces their numbers in the peripheral circulation, as 
shown by the reports of numerous observers. Bristowe and Cope- 
man in a series of attacks induced in the same patient found a maxi- 
mum loss of red cells of 129,000 to 824,000. In an idiopathic case 
of moderate severity Grawitz found a loss of 1,130,000 following a 
single paroxysm. Usually the reduction in cells is not so marked, 
and Grawitz has explained this fact by showing that, from vasomotor 
spasm and increased diuresis during the attack, the blood is consider- 
ably concentrated, since the dry residue of the blood and serum is 
considerably increased after the seizure, notwithstanding the loss of 
cells. For the same reason and because the Hb is not immediately 
removed from the serum, the percentage of Hb is not excessively low 
during or immediately after the paroxysm. Indeed, Frazer found 
an increase of 10 per cent, of Hb about an hour after the beginning 
of an attack. Usually there is a loss of 5 to 10 per cent. Ponfick 
claimed that at least one-sixtieth part of the Hb of the blood must 
be lost before it will appear in the urine. 

The appearance of the blood in the stained specimen taken shortly 
after the paroxysm usually gives evidence of active destruction of 
blood. The red cells may fail to form rouleaux, although having 
possessed this property just before the attack. Many very pale or 
shrunken or fragmented cells have been observed in some cases, while 
in others the red cells were found to contain a normal amount of Hb. 
After repeated attacks megalocytes appear. On the other hand, 
Kohler and Obermayer found no morphological changes in a case 



HEMORRHAGIC DISEASES AND INTOXICATIONS. 369 

losing 650,000 red cells and 10 per cent. Hb. The presence of poly- 
chromatic cells or of granular degeneration of red cells has apparently 
not been reported, but in a case of blackwater fever, shortly before 
death, the writer found the latter form of degeneration in extreme 
degree. Frank noted in a paroxysmal case that the red cells in the 
fresh condition looked pale and brownish. The serum has been 
found distinctly tinged by the dissolved Hb. Bristowe and Cope- 
man found pigment granules, crystals of Hb, and colorless crystals 
resembling Charcot's. 

The LEUCOCYTES were found by Frazer moderately increased 
(21,000), but the majority of observers have reported them as normal, 
or, if above normal, as being little affected by the paroxysm. The 
blood plates have been reported as very much increased (Frazer, 
Mesnet), as seems very probable from the extensive destruction of 
red cells. 

The COAGULABILITY OF THE BLOOD is normal or increased. 
Hayem^ noted that the rapidly formed clot softens very soon, which 
Chvostek finds is observed in other conditions. The resistance of 
the red cells, as determined by Hamburger's method, was found by 
V. Hoff to have fallen to 38 per cent. NaCl, and Sabrazes, using 
Malassez's method, also found it reduced. 

Following the destruction of red cells there is usually a reduction 
in the alkalinity of the blood. Kobert believes this to be due 
to setting free of phosphoric and glycerin-phosphoric acids during 
the separation of oxyhemoglobin from the red cells. 

The regeneration of the blood is, in uncomplicated cases, very 
prompt, Bristowe and Copeman finding an increase of 500,000 cells 
after five days, and 600,000 after six days. Most confirmed cases, 
however, suffer from a moderate or marked grade of chronic anemia, 
sometimes associated with enlargement of the spleen. 

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Brown. Amer. Jour. Med, Sci., vol. cxxii, p. 770. 
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24 



370 COXSTITUTIOXAL DISEASES. 

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Frankel. Deut. med. Woch., 1889, p. 22. 

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Grandidier. Die Hemophilie, Leipzig. 1877. 

Guarnieri. BuU. d. Soc, Lancisiana, ^Nlay 24, 1888. 

Hamilton, Yates. Montreal Med. Jour., 1897, p. 117. 

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HEMOBBHAGIC DISEASES AND INTOXICATIONS. :J71 

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Marchand. Archiv f. exper. Path., 1887, Bd. 22, 23. 

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Zalesky. Arch. f. exper. Path., 1897, Bd. 23, p. 77. 



CHAPTER XVIII. 

MISCELLANEOUS CONSTITUTIONAL DISEASES. 
DIABETES MELLITUS. 

The results of older observers led to conflicting opinions regarding 
the condition of the blood in diabetes^ since it appeared that in cases 
of about equal severity the Hb, red cells, and albumins might in one 
patient be increased and in another diminished^ or might vary con- 
siderably at different times in the same patient, not infrequently 
rising above normal. 

The studies of Henocque were among the first showing that while 
individual differences may be considerable, yet in a series of cases 
the Hb does not vary greatly from the normal. Leichtenstern, find- 
ing an excess of Hb in an advanced case and a diminution in an 
early case, was led to refer the anomaly to the effects of diuresis in 
concentrating the blood. Although the extent of the diuresis depends 
largely upon the amount of sugar secreted, a very close relation 
between the Hb of the blood and the sugar of the urine has not 
apparently been established. Yet the above logical explanation has 
been generally accepted, and the marked changes observed in the 
blood of many diabetics may be referred to the uncertain balance 
between the amount of water absorbed and that excreted in the urine. 

In the late stages of the disease other factors enter to further dis- 
turb the condition of the blood. General failure of nutrition belongs 
to the advanced disease and the blood must suffer proportionately. 
Yet even in extreme cases the anemia is commonly masked by the 
concentration of the blood through diuresis, and it becomes necessary 
to class the blood of advanced diabetes, with excess of Hb and cells, 
as among the examples of oligemia or oligoplasmia. 

From these considerations it is evident that the estimation of Hb 
and the counting of red cells are of little use in diabetes unless very 
carefully controlled by reference to the diet and urinary excretion. 
Thus, the writer found in an emaciated anemic case, with advanced 
phthisis, 78 per cent, of Hb and 4,100,000 red cells. In most 
reported cases in which the daily urine measured over three litres 
the red cells approached the normal figure. 

In Grawitz's case of coma the red cells rose from 4,900,000 three 
weeks previously to 6,400,000 five hours after the onset of the coma, 
and the dry residue of the blood from 21.4 per cent, to 24.75 per 
cent. Possibly the result was in part referable to cyanosis. Haber- 
shon reports three cases of coma with excess of red cells (maximum, 
6,640,000). They all suffered from dyspnea, but in one the cells 



MISCELLANEO US CONSTITUTIONAL DISEASES. 373 

were lower than they were a week before death. In a cyanotic coma- 
tose case examined by the writer there were 6,800,000 red cells. 

The general character of the blood in diabetes is well illustrated 
in the cases reported by James, as follows : 

Specific gravity. 

No. Red cells. Hb. Roy's method. 

1 6.73 m 1.056 

2 6.10 61 1.059 

3 4.80 5S 

4 5.25 60 

5 5.60 65 

6 3.55 52 1.054 

7 52 1.060 

8 5.30 75 1.056 

9 6.28 108 1.055 

10 5.38 96 1.055 

11 5.64 112 1.056 

12 6.20 112 1.057 

13 4.46 55 1.054 

14 6.00 96 

James concluded from these results that the excess of red cells in 
diabetes cannot result from concentration of the blood, otherwise the 
specific gravity would have been higher. Yet, considering the per- 
centage of the Hb, the gravity in the above cases is distinctly above 
the usual figure, indicating relative an hydremia with marked reduc- 
tion of Hb, but with slight loss of red cells. 

Leucocytes. The leucocytes, in the average hospital case if 
uncomplicated, are normal, subnormal, or moderately increased. In 
seven of twenty untreated cases Habershon found less than 10,000 
leucocytes, in the others a leucocytosis reaching a maximum of 
19,800, and being rather uniformly present in the severer cases. 
With the advent of severe symptoms he found the leucocytes to 
increase, and in three cases of coma there was pronounced leucocy- 
tosis (maximum 28,500). Cabot found no leucocytosis in thirteen 
cases, and only 4200 in a comatose patient. The writer observed 
leucocytosis in four patients, one comatose, but autopsies revealed 
phthisis, suppuration, or pneumonia. 

Chemistry. The chief chemical alteration demonstrated in the 
blood is a pronounced increase in sugar. While normal blood con- 
tains 0.05 to 0.15 per cent, of sugar, Pavy and Seegen have found 
as much as 0.6 per cent, in severe diabetes, and Frerichs found the 
sugar of the blood to vary between 0.38 to 0.44 per cent., while that 
of the urine amounted to 5.5 to 8.4 per cent. Naunyn obtained 0.7 
per cent, in the blood of a fatal case in Avhich the urine contained 4 
per cent. In Klemperer's^ ^^ renal diabetes ^^ the sugar of the blood 
remains normal. 

Henriques and Kolish have lately claimed that an excess of pre- 
formed sugar exists in the blood only in alimentari/ glifcosuria, while 
in diabetes the preformed sugar of the blood is but slightly above 
normal. They find, however, that in diabetes the blood contains a 
marked excess of jecorin in combination with albumins which, 
during excretion, is split up into su^ar and lecithin. 

Lepine and Barral believe that diabetes results from the failure 



374 CONSTITUTIONAL DISEASES. 

of a glycolytic ferment elaborated by the pancreas and normally 
present in the blood, but this theory has not been demonstrated 
(see Glycolytic Ferment). 

Fat, occurring in traces in normal blood, is usually increased in 
diabetes and may become extremely abundant. Usually microscopic 
examination is required to demonstrate the minute extracellular 
globules in specimens stained by osmic acid, but often the fat rises 
to the surface in demonstrable quantity if the specimen is centrifuged 
in the liematokrit, and occasionally the blood is milky from the 
abundance of fat. Its origin in the blood is not understood, but 
Van ISToorden says that it is not connected with a previous ingestion 
of fat, as is the case with some other forms of lipemia. In one case 
Aschoff separated 3.44 per cent, of fat from the blood. 

Grlycogen in the blood of diabetes has been demonstrated in marked 
cases by Gabritschewsky, who found it both in plasma and leucocytes, 
but the significance of the brownish, extracellular granules has been 
brought into question. Livierato could find but little glycogen in 
the plasma and none in the leucocytes. Futterer claims to have 
demonstrated in the brain and medulla many tlirombi composed of 
glycogen. Of five cases of diabetes the w^'iter found in eacli a few 
leucocytes with many glycogen granules, while in the plasma were 
brownish-staining granules of which the significance seemed uncer- 
tain. The glycogen-holding leucocytes were less abundant than in 
cases of pneumonia. 

Alkalinity. The alkalinity of the blood in normal subjects varies 
between 300 and 400 mg. of NaOH per 100 gm. of blood, and 
is always diminished in patients who are much reduced in strength. 
In diabetes, when the patients are suffering little general disturbance, 
the alkalinity of the blood has been found to be very slightly reduced 
(Minkowsky, Kraus, Lepine). When diabetes reaches the stage 
of excretion of oxybutyric acid in the urine, the alkalinity of the 
blood has been found to be lower than in any other known condition, 
falling as low as 40 mg. of XaOH per 100 of blood (Yan Noorden). 
In diabetic coma Minkowsky found as low as 3.3 vol. of CO2 per 
100 of blood. It is especially in diabetes that a distinction between 
alkalinity and the alkali-tension referable to diffusible alkali appears 
to be of importance, as chiefly in diabetic coma did Brandenburg 
find a marked reduction in the alkali-tension of the blood. 

This relative acidemia has been referred to the presence in the 
blood of various acid products of proteid metabolism, ^-9-oxybutyric 
and other fatty acids.* These acid products are supposed to act either 
as direct poisons, or indirectly, by lowering the alkalinity of the 
blood. The basis of this theory is found partly in the demonstra- 
tion of diminished alkalinity in the blood, but largely in the abun- 
dance of these acids or their salts in the urine. 

OBESITY. 

The majority of healthy obese subjects show an excess of Hb, as 
is clearly indicated by the extensive observations of Kisch, who found 



MISCELLANEOUS CONSTITUTIONAL DISEASES. 375 

a notable excess and maximum of 120 per cent, of Hb in 79 
of 100 fat subjects, while in the other 21 it was diminished, 
reaching 55 and 60 per cent, in some instances. The existence of 
distinct anemia in some apparently healthy fat subjects had long 
been accepted, but the opinion was rendered much more certain by 
Leichtenstern's observation of four such cases, showing considerable 
reduction of Hb. Oertel also found an excess of 5 to 8 per cent, of 
Hb, and Grawitz reported an increase of the dry residue of the blood 
in very fat subjects. It appears, therefore, that there is a distinct 
tendency toward true plethora associated with obesity, while the 
anemia occasionally observed, as in the majority of Kisch's anemic 
cases, is referable to other causes. 

Grawitz, in two cases, observed a considerable reduction in dry 
residue both of the whole blood and of the serum, as a result of a 
course of treatment which reduced the body weight ten to twelve 
pounds. 

That the plethora of obesity is sometimes more apparent than real 
is suggested by the constant perspiration, frequent dyspnea, and ten- 
dency toward venous congestion, from which these subjects suffer. 

ADDISON'S DISEASE. 

Established cases of this disease are usually attended with a severe 
grade of anemia. In four cases reported by Tschirkoff the red cells 
before treatment numbered from 2,733,000 to 3,280,000. In three 
of Cabot's cases, and in four examined by the writer, the same grade 
of oligocythemia was observed, while Neumann reported more severe 
anemia with 1,120,000 red cells in one case. Morphological changes 
in the red cells are not marked, but microcytes are sometimes quite 
abundant. 

Leucocytes are commonly diminished, sometimes slightly increased, 
and are subject to the usual variations of secondary anemia. Eosino- 
phile cells were present in high normal proportions in Cabot's and 
in the writer's cases, while Cabot found some eosinophile myelocytes 
in one case. 

Neusser claims that the relative lymphocytosis is an unfavorable 
sign in Addison's disease, and that it commonly increases as tlie 
patient gets worse. Hamel doubts this statement, as in a case under 
his care there were once 52 per cent, of lymphocytes, declining to 
38 per cent, when the patient died. Hamel believes that oligemia 
is an essential feature of the disease, and accounts for the anemic 
appearance of patients whose blood is of normal quality. He and 
Neusser regard distinct changes in the quality of the blood as indica- 
tions of some lesion of the adrenals or viscera other than tuberculosis. 

Opposed to the typical cases are others reported in which the red 
cells were in excess of 5,000,000, reaching, in Neumann's observa- 
tion, the remarkable figures of 7,700,000, while Tscliirkotf found 
that the Hb in early cases might exceed the normal. Lucatello 
found the iron content of the blood hioher than the Hb would lead 
one to expect. It appears likely that disturbances in the circulation 



376 CONSTITUTIONAL DISEASES. 

may be responsible for some of these anomalous results, but the sub- 
ject requires further observation. 

The deposits of pigment in Addison's disease have been referred 
by Riehl and Afanissiew to the results of minute thrombi and hemor- 
rhages in the superficial vessels, and Afanissiew observed the disin- 
tegration of red cells in local pigmented areas. V. Kahlden, however, 
showed these lesions to be inconstant and probably of secondary 
significance. 

An interesting contribution to the pathology of Addison's disease, bearing 
on this point, has been furnished by Tschirkoff", who examined the blood of 
two cases with special reference to the pigments, by means of Glan's spectro- 
photometric method, by which he was able to estimate the relative amounts of 
oxy-Hb and reduced Hb. By this method he found in advanced cases a 
much greater proportion of reduced Hb than is present in normal blood, and 
at times more reduced Hb than oxy-Hb. During improvement he found an 
increase in the proportion of oxy-Hb at the expense of the reduced Hb, but 
without corresponding increase in the total Hb of the blood. He found evi- 
dence pointing to the presence of methemoglobin in the blood, but could not 
observe any quantitative relation between these changes in the Hb of the 
blood and the pigmentation of the skin. He concluded that Addison's dis- 
ease is associated with a qualitative rather than quantitative change in the 
hemoglobin of the blood, with a corresponding failure to furnish oxygen to 
the tissues. His results have not yet been verified. 

GOUT. 

From the comparatively few recorded observations it is evident 
that acute gout has little effect upon the red cells and Hb of the blood, 
in which respect it differs from acute rheumatism. In chronic gout, 
also, Duckworth found cases with inappreciable anemia and con- 
cluded that when the disease is associated with anemia the condition 
of the blood is referable principally to complications such as hemor- 
rhage, nephritis, lead poisoning, bad hygiene, etc. The writer found 
uniform but moderate anemia in a series of chronic cases examined 
at Roosevelt Hospital, the patients all coming from the poorer classes. 

Leucocytes. The leucocytes are increased in acute attacks. 
Watson observed marked leucocytosis in an acute attack with a con- 
siderable percentage of large mononuclear vacuolated cells without 
neutrophile granules, which he regarded as myelocytes. Da Costa 
also observed slight leucocytosis, 14,000, and a few myelocytes. In 
the chronic cases leucocytosis of moderate grade may be observed, 
but it is difficult to determine its relation to the gouty process, as 
many of these patients suffer from other complaints. !N^eusser^ men- 
tions the usual presence of mixed leucocytosis in a series of 100 cases 
of the uric acid diathesis. 

Chemistry. The chemistry of the blood in gout has for many 
years been the subject of extensive investigation, and while the 
presence of abnormal principles has been demonstrated an important 
relation of these principles to the pathogenesis of the disease has not 
been established. 

Garrod first demonstrated an excess of uric acid in the shed blood, 
finding 0.025 to 175 grains of uric acid for 1000 grains of serum, in 



MISCELLANEOUS CONSTITUTIONAL DISEASES. ?j'J'] 

five cases during and shortly after the attack, and this uricacidemia 
has been noted by Salomon/ v. Jaksch, and Klemperer.^ Recently 
Magnus-Levy^ failed to find, in several cases, any constant variations 
in the amount of uric acid which might be regarded as an increase. 
Watson also failed to find any increase in uric acid in the blood or 
loss in alkalinity during acute attacks, while the excretion of uric 
acid w^as increased. 

Garrod perfected a ready clinical method for the demonstration of 
uric acid in the blood or serum of gouty patients, commonly known 
as the '^ thread test." 

One to two drachms of serum from fresh blood drawn from a vein are placed 
in a broad, flat dish, about three inches in diameter and one-third of an inch 
deep, and to it are added six minims 33 percent, acetic acid to each drachm of 
serum. A couple of old but clean linen threads are submerged in the fluid and 
the vessel is allowed to partially evaporate at room temperature for thirty-six to 
sixty hours, when the threads will be found to have gathered minute crystals of 
uric acid, if any considerable trace is present in the blood. They may be 
washed in water and freed from any adherent phosphate and identified under 
the microscope. Garrod found that crystals begin to deposit on the thread 
when the serum contains 0.025 grain of uric acid per 1000, and become very 
numerous with 0.08 grain per 1000. The test must be carefully performed 
and may fail, especially from too rapid or prolonged evaporation, or from heat- 
ing above 75° F. Serum obtained from a blister may be used, but not when 
obtained from the neighborhood of an inflamed joint. 

Excess of uric acid in the blood is not, however, pathognomonic 
of gout, being absent in some undoubted cases (Duckworth), and 
being abundantly present in many other conditions, such as pneu- 
monia (Salomon^), and other conditions with leucocytosis, emphysema, 
nephritis, severe anemia (v. Jaksch^), leukemia (Magnus-Levy^), and 
after a diet rich in nucleoproteids (Weintraud). 

Alkalinity. The assumption by Garrod that an excess of uric acid 
in the blood is associated with diminished alkalinity has not been 
supported by late observations. Klemperer,^ estimating the alka- 
linity by the content of the blood in CO2, found no distinct varia- 
tions from the normal in three cases during the attack. Luff, using 
Wright's method, also failed to find any loss of alkalinity during the 
course of an acute attack, and Magnus-Levy, using Lowy's method, 
failed to find any constant variations in a series of sixteen cases 
examined at various periods. Pfeiffer, v. Jaksch, and Drouin also 
failed to find any constant reduction. 

From the recent studies of the chemistry of the blood in gout, 
it is evident that Garrod's theory of the nature of the disease must 
be abandoned. 

OSTEOMALACIA. 

The usual condition of the blood in osteomalacia appears to be that 
of moderate chlorotic anemia. Such cases are reported by Eisenhart, 
Tschistowitch, and others, while Seligman, in an advanced case, 
found 41 per cent, of Hb. 

Red Cells. The red cells are usually normal or very slightly 
reduced. Shortly after abortion Tschistowitch's case showed 8,100,000 
cells, but the numbers increased rapidly, later to oscillate between 



378 CONSTITUTIONAL DISEASES. 

3,400,000 and 6,800,000. One of Eieder's cases had 3,800,000 
cells, another 4,900,000. 

Leucocytes. The leacocytes have varied from subnormal to 
moderately increased numbers. The leucocytes are usually very 
numerous, an excessive proportion (maximum, 56 per cent.) having 
been found by Tschisto witch, while Ritchie observed moderate 
lymphocytosis. Myelocytes have been found by Neusser and by 
Tschistowitch. 

Xeusser^ proposed to divide cases of osteomalacia into two groups, 
one showing myelocytes in the blood, the other showing high propor- 
tions of eosinophile cells, of whiSh he had seen examples. High 
normal proportions of eosinophiles have been found by several 
observers, but not by others, viz., Fehling, Sternberg, and Chrobak, 
who were probably looking for a distinctly abnormal number. In 
Tschistowitch's case their numbers varied greatly during the year 
over which his observations extended. 

Chemistry. The alkalinity usually varies between normal limits 
(Limbeck), but has been found both increased and diminished. 
Lactic acid has never been fully demonstrated in the blood. Peters 
claimed to have found in the blood a nitrifying micro-organism, 
cultures of which produced in dogs a condition resembling osteo- 
malacia. This claim has not been established. 

RACHITIS. 

The state of the blood in rachitis varies with the extent and 
severity of the primary disease and is markedly affected by compli- 
cations. Xearly all series of cases reported contain some examples 
of pronounced rachitis in which the red cells were nearly normal and 
the Hb very moderately reduced, and some observers, as Felsenthal 
and Morse, did not meet with severe anemia in any case. Nor does 
it appear that the anemia bears a very close relation to the extent of 
the disease, although as a general rule the advanced cases with 
enlargement of the spleen show greater anemia than do those without 
involvement of the viscera (Monti, Berggrun). It is agreed on all 
sides that the disease is not associated with any peculiar type of 
anemia, although the hyperemia of the bone-marrow might be ex- 
pected to yield an unusually large number of nucleated red cells. 
Yet these cells are apparently not more abundant in rickets than in 
congenital syphilis (Monti), while Gundobin found the same grade 
and type of anemia in rachitic as in other poorly developed infants. 
Rachitis figures about equally with syphilis, etc., in the etiology of 
V. Jaksch's anemia. 

The existence of rachitis in patients with normal blood raises a question as 
to the cause of the anemia usually found in the disease, and the conclusion 
seems justified that the anemia of rickets is largely referable to the general 
malnutrition of the patient and to a variety of complications, especially gas- 
troenteritis. Moreover the pathological nature of the disease renders it 
extremely improbable that the lesion in itself has very marked effect upon the 
blood. So far as our present knowledge goes, the anemia of rickets is practi- 
cally that of marasmus and gastroenteritis. 



3nSCELLANE0US CONSTITUTIONAL DISEASES. 379 

Simple chlorotlc anemia is the usual condition of the blood of 
rachitic children. No other forms were encountered among the 
cases of Felsenthal and Morse^ most of which were described as of 
moderate grade ; and a few examples of the same type have been 
described by others. Although the red cells may be above 5,(;00,000;, 
the lib is invariably reduced, the color-index frequently falling as 
low as in primary chlorosis. Morse found an average Hb-index of 
0.7, and Felsenthal obtained only 50 per cent, of Hb in one case 
with over 5,000,000 cells. The usual morphological changes in the 
red cells are to be observed, and a few nucleated red cells are nearly 
always to be found in the young subjects. The leucocytes in cases 
with mild anemia are usually found at the higher normal limits or 
distinctly increased. Rickets does not appear among Monti's cases 
of simple anemia without leucocytosis. 

Grave secondary anemia is observed in many cases of rachitis in 
which there are almost always some serious complications. Although 
the progress of rachitic anemia is sometimes moderately rapid, the 
cause of the destruction of red cells is not always apparent, V. Jaksch 
saw the red cells fall from 1,600,000 to 750,000 within three months, 
w^hile Luzet saw a reduction of 500,000 cells in three weeks. 
Usually the loss of cells occurs more slowly, and in the grave forms 
of anemia the impoverishment of the blood is usually attended with 
enlargement of the spleen and often of the liver. 

The changes in the red cells are then similar to those of other 
forms of severe secondary anemia of chronic course, but poikilocytes 
and nucleated red cells are unusually numerous. The Hb-index 
varies. In a few instances, especially those of more rapid course, the 
Hb is deficient, but usually the Hb-index rises and may become 
abnormally high. Thus, Monti and Berggrun found 50 to 55 per 
cent. Hb with 2,350,000 cells. In all cases of this type there is 
leucocytosis. 

Progressive pernicious anemia appears to be a relatively infrequent 
complication of rickets. In eleven cases of pernicious anemia in 
young children or infants, collected by Monti and Berggrun, rickets 
existed or was mentioned in only two, and one of these was compli- 
cated by congenital syphilis. The writer has had a similar experi- 
ence, never having found the well-marked characters of progressive 
pernicious anemia in a rickety child. 

Leucocytes. It has already been shown that in many mild cases 
of rickets the leucocytes do not exceed the normal limits for young 
infants. The slight excess over 10,000 seen in most of the mild 
cases reported is not, as Cabot points out, abnormal for infants. 
Felsenthal found 30,000 white with 4,000,000 red cells in one mild 
case in which no complication was noted. 

In the severer cases leucocytosis is nearly constant, but does not 
usually exceed 30,000. Yet Luzet believes that there are all grades 
of the leucocytosis of rickets up to that of leukemia, where it is cer- 
tainly difficult at times to distinguish the leucocytosis of a rachitic 
anemia from that of v. Jaksch's anemia. The lymphocytes are 
usually quite numerous, but not often excessive for the age. ^lorse 



380 CONSTITUTIONAL DISEASES. 

found an average of 43 per cent, of lymphocytes in twenty rachitic 
children under two years of age. Distinct lymphocytosis was 
observed by Rieder, Weiss, Monti and Berggran, and Morse, and, 
while probably not uncommon in young subjects, is without special 
signifiance. 

Eosinophile cells are often relatively numerous. Morse found an 
average of 3 per cent. They may be distinctly increased, as Hock 
and Schlesinger found 20 per cent, in one subject and Weiss 16 per 
cent, in another, or they may be scanty (Rieder, Cabot). 

The conditions leading to excess of leucocytes in rickets are not 
well understood. Limbeck refers the excess principally to the 
gastroenteritis which is often present. Whilst most cases with 
leucocytosis show hyperplastic splenitis, these two conditions are 
most probably separate effects of a common cause. ^Xot all cases 
with enlarged spleen show leucocytosis, which is commonly absent 
in pronounced cases of '^ splenic anemia " in infants. Luzet, how- 
ever, connects the excess of leucocytes with the hyperplasia of the 
spleen. 

It seems not improbable that the hyperemia of the marrow may tend 
to discharge an unusual number of white cells into the circulation, 
a possibility which is favored also by the large number of nucleated 
red cells commonly seen, by the frequent presence of a few leucocytes 
with mitotic nuclei (Hock, Schlesinger), and by the nearly constant 
occurrence of myelocytes. 

Chemistry. The specific gravity of the blood was reduced in pro- 
portion to the loss of Hb in the cases of Hock and Schlesinger. 
Even in patients who appeared otherwise in good health the specific 
gravity of the blood was distinctly reduced in twelve cases examined 
by Felsenthal and Bern hard. 

MYXEDEMA. 

The anemia of myxedema, in the majority of pronounced and 
untreated cases, is of the secondary chlorotic type, with slight leuco- 
cytosis, and of moderate grade. Bramwell observed well-marked 
anemia in twenty-six of thirty-three cases. Of twenty-three cases 
collected by Murray the blood was normal in seven, while in the 
cases of Cabot and in those of Kraepelin there was no anemia. The 
most severe anemia recorded was that of Le Breton's case, in a child 
of three years, with 1,700,000 cells, 65 per cent, of Hb, and 4500 
leucocytes. Many other cases have shown a reduction of the red 
cells to about 3,000,000 (Bramwell, Putnam, and two cases of the 
writer). Kraepelin noted by careful measurements a distinct increase 
in the diameters of the red cells in four cases, and claimed this feature 
to be one of the typical symptoms of myxedema. The chemical 
examinations of the blood of these patients supported this conclusion 
by showing excess of solids. Le Breton also noted a similar condition 
in the blood of his case, but the patient was very anemic (1,700,000 
cells). Vaquez found the majority of cells increased in size and 
varying from ^[jl to 14^« in diameter. Treatment caused no increase 



MISCELLANEOUS CONSTITUTIONAL DISEASES. 381 

in the number or change in size of the cells. Cabot failed to 
find any such changes in the red cells of three cases. When present 
it is probably referable to the increased venosity of the blood, which, 
according to Horsley, is commonly present in myxedema. The Hb 
is usually moderately reduced, but less than in most other forms of 
secondary anemia. In Le Breton^s case the Hb-index was abnor- 
mally high (1.8), but since large nucleated red cells were present 
the condition of the blood seems to accord with that of pernicious 
anemia. 

In two of Kraepelin's cases, while the Hb by Fleischl's method 
was not excessive (5,400,000 to 5,600,000 cells, 93 to 98 per cent. Hb), 
by the spectrophotometric method an abnormal quantity of blood 
pigment was demonstrated. The specific gravity was also abnor- 
mally high. In several other cases, even when the red cells were 
considerably deficient, the Hb-index was normal or increased (Bram- 
well). Putnam reports a few myelocytes in one case in which the 
blood was otherwise nearly normal. 

Thyroid treatment has usually been followed by marked improve- 
ment in the blood. In six weeks Kraepelin^s case gained 700,000 
red cells, and nucleated red cells and leucocytes disappeared. Putnam 
observed polythemia (5,700,000) after six months' treatment. Marked 
anemia followed the administration of overdoses of thyroid extract 
in one of Bram well's cases, but on smaller doses the patient did well. 
The course of the blood changes in this case was as follows : 

Red cells. Hb. 

October 28 (before treatment) 3,800,000 65 per cent. 

November 28 (after acute thyroidism) . , . 2,600,000 54 " 

December 21 (smaller doses) 3,800,000 68 

January 13 4,30J,000 70 

Leucocytes are usually not increased, but in six of Murray's twenty- 
three cases there was leucocytosis. In uncomplicated cases without 
severe anemia it appears to be nearly always absent. The propor- 
tions of the various leucocytes are not altered. Cabot found 5 and 

4.4 per cent, of eosinophiles in two cases, but Schmidt found only 

1.5 per cent, of these cells. Putnam reports a few myelocytes in 
one case in which the blood was otherwise nearly normal. 

Chemistry. Very numerous and elaborate studies of the chemis- 
try of the blood in myxedema, and especially in thyroidism, have 
failed as yet to demonstrate the exact nature of this peculiar toxemia. 
Halliburton, in 1885, demonstrated mucin in the blood of thyroid- 
ectomized dogs, an observation which has been fully confirmed, and 
Levine has recently produced peculiar chronic toxemia by injec- 
tion of mucin in animals after partial thyroidectomy, although 
similar injections in healthy animals were innocuous. Yet in the 
human subject an excess of mucin in the blood has not been demon- 
strated. 

The chemical analysis of Kraepelin's cases, by Schneider, showed 
the exaggerated effects of chronic venosity of the blood, a condition 
first noted clinically in mvxedema bv Horslev. Here there was con- 



382 CONSTITUTIONAL DISEASES. 

siderable increase in specific gravity of the blood (1.0625 to 1.0636) 
and of the serum (1.0317 to 1.0329), while the dry residue of whole 
blood, serum, and red cells was also increased. 

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Seligman. Cent. f. Gyn., 1893, pp. 374, 649. 
Sternberg. Zeit. f. klin. Med., Bd. 22, p. 265. 
Tscliirkoff. Zeit. f. klin. Med., Bd. 19, Sup., p. 87. 
Tschistowitch. Berl. klin. Woch., 1893, p. 919. 
Vaquez. Prog. Med., 1897, p. 180. 
Watsoji. Brit. med. Jour., 1900, I., p. 10. 
Weintraud. Deut. med. Woch., 1895, V. B., p. 185. 
Weiss. Jahrb. f. Kinderheilk. Bd. 35, p. 146. 



CHAPTER XIX. 

NERVOUS AND MENTAL DISEASES. 

MANIA, GENERAL PARESIS, MELANCHOLIA, DEMENTIA, 

EPILEPSY. 

The blood of inmates of insane asylums has been the subject of 
much careful study. 

In 1873 Sutherland examined the blood of 149 insane patients, 
finding in four of them grave secondary anemia with leucocytosis. 
Excess of leucocytes occurred in many other milder or earlier cases. 

McPhail contributed the first scheme of the blood changes in 
general paresis^ finding from a study of fifteen cases that : 

1. The Hb was moderately low on admission (62.70 per cent.), 
improved for a time, owing to the better hygienic conditions pre- 
vailing in the institutions, but fell (52.66 per cent.) in the terminal 
stages of the disease. 2. The red cells diminished steadily with the 
progress of the disease, reaching in one case 3,400,000. 3. Leuco- 
cytosis (minimum, 12,700) was noted in all cases, progressed with 
the disease, and reached a well-marked grade in the terminal stages, 
27,700 to 36,600. 

Lewis, Steele, Seppili, and others obtained results very similar to 
the above and added many new details. Smyth examined the blood 
in cases of melancholia, epilepsy, general paresis, and secondary 
dementia. He found the red cells as a rule below the normal, while 
the Hb was reduced in much greater degree. The average results 
obtained were as follows : 



Melancholia 
Epilepsy 

General paresis . 
Secondary dementia 









Specific 


During 


Cases. 


Hb<. 


Red cells. 


gravity. 


convulsions. 


10 


69.7 


4,684,000 


1.0572 




50 


62.8 


4,520,000 


1.0568 


1.0596 


40 


68.7 


4,700,000 


1.0605 




12 


53.7 


4,070,000 


1.0612 





The more marked anemia, with high specific gravity, of secondary 
dementia, and the increase of specific gravity after epileptic convul- 
sions, which was not invariable, are specially worthy of note. 

Winckler also found a distinct loss of Hb, especially in the 
depressed forms of insanity. Paroxysms of mania or of melancholia 
caused a loss of both cells and Hb, which was restored after the 
recovery from the attack. Terminal dementia was associated with a 
progressive anemia. Capps examined twelve cases of general paresis 
in which the red cells never fell below 4,000,000, while never reach- 
ing 5,000,000 (average 4,789,000). The Hb varied between 73 and 
92 per cent, (average 85 per cent.), and the specific gravity between 



XEBVOUS AXD 3IENTAL DISEASES. 385 

1.058 and 1.066. Convulsions appeared to concentrate the blood. 
Jelliffe, working at the Binghampton State Hospital, altitude 400 
metres, found moderate polycythemia in fourteen of seventeen cases, 
but the Hb was usually reduced, in one case to 52 per cent. The 
specific gravity ranged from 1.047 to 1.060. Langdon and Bam- 
ford, at the Hudson River State Hospital, obtained in a reasonably 
short time twentv verv anemic cases of melancholia, with red cells 
between 2,000,000 and 3,000,000, Hb between 60 and 85 per cent. 

Treatment by bone-marrow rapidly improved the condition of the 
blood. Severe anemia, red cells 2,500,000, Hb 25 per cent., is also 
reported by Howard in a case of terminal dementia, while in Steele's 
thirty-five cases of melancholia the average of red cells was 3,000,- 
000, of Hb 75 per cent. 

The Leucocytes. In early cases there is usually no leucocytosis, 
and the uniform tendency to leucocytosis observed by McPhail has 
not been found by all subsequent observers. Smyth reported an ex- 
cess in many cases, but without relation to the symptoms of the disease. 

Most of Capps' patients had leucocytosis, as did also the very 
anemic subjects examined by Langdon and Bamford, while in the 
tables of Jeiliffe and Somers leucocytosis was absent in the majority 
of cases. Leucocytosis is more frequent when there is anemia, in 
the last stages of the disease, and it has been found rather more fre- 
quent in the more acute forms of insanity and in terminal dementia. 
Somers found an average of 8315 leucocytes in nineteen cases of 
mania ; 7947 in nineteen cases of melancholia ; 10,473 in nineteen 
cases of dementia, and 8800 in five cases of general paresis. In 
sixteen cases of epilepsy Kuhlmann obtained distinct leucocytosis in 
only one (14,000). Pease followed the leucocytosis long enough to 
show that it is often transitory. 

The proportions of the various forms of leucocytes show no constant 
or significant variations. When the total numbers are increased the 
polynuclear forms are usually most affected. Lymphocytosis is fre- 
quently observed, especially in epilepsy. The eosinophiles show irregu- 
lar variations, being absent in some cases, reaching high normal figures 
in others, while Roncorini found a marked excess, up to 25 per cent., 
in maniacal cases. Krypiakiewicz also found an increase of these cells 
in the more acute forms of insanity, and comparatively low propor- 
tions in the chronic forms. Capps could not find that the restless- 
ness of the patient was always connected with any increase in eosino- 
philes. 

To recapitulate the results of the above studies, it has been shown 
that the common forms of insanity may develop in anemic subjects 
or in those whose blood is normal. The disease may run its course 
without anemia, but usually the state of the blood accords with the 
general state of nutrition. In some cases, especially of melancholia, 
the blood suffers more than the general nutrition. 

Leucocytosis is frequently observed, especially in anemic subjects, 
in late stages, and after convulsions. Convulsions may concentrate 
the blood and induce leucocytosis. Acute mania is not associated 
with any specific changes in the morphology of the blood. 



386 CONSTITUTIONAL DISEASES. 



BERIBERI. 



This form of iufectioiis neuritis is often associated with severe or 
even pernicious anemia (Spencer), but in the cases which reach 
America the anemia is usually moderate and of the chlorotic type. 
In three recentlv imported cases of the disease, each with moderate 
fever (100° to i01.5° F.), the red cells ranged between 3,000,000 
and 3,500,000, and were very deficient in Hb, while showing no 
other changes, except for the presence of microcytes. Leucocytosis 
was absent and the eosinophiles were not increased. Cabot records 
an afebrile case with 3,900,000 red cells, 48 per cent. Hb, and 7800 
leucocytes. 

Daubler found normal numbers of red and white cells, but increase 
of fat, in the blood of three cases. 

Numerous attempts to demonstrate the infectious agent in beri- 
beri are thus far negative. Various bacteria have been demonstrated 
in the blood postmortem. The latest contribution is that of Fajardo, 
who believes that he has seen in the red cells of fifty-nine cases a 
protozoan resembling the parasite of Texas fever, but smaller and 
more difficult to stain. 

Host is reported to have found a diplobacillus in the rice eaten by 
natives suffering from beriberi, and the same bacillus in the blood, 
cerebrospinal fluid, and inflamed nerve sheaths of beriberi patients. 

Stanley planted 1 c.c. of blood in each of thirty cases and found 
no growth, while in the smears there was no trace of the hematozoon 
described by Fajardo. Affleck also reports negative bacteriological 
studies of the blood. 

CHOREA. 

The coincidence of St. Yitus^ dance and chlorosis was such a fre- 
quent clinical picture that the older writers regarded the anemia as 
one of the essential causes of such nervous manifestations. Although 
this view has been proven untenable it remains true that anemia and 
chorea have many common antecedents, that the blood in chorea 
usually shows a slight impoverishment, and that anemia is a very 
frequent predisposing cause of chorea. 

Burr found moderate chlorotic anemia in all of thirty-six cases, 
but anv severe grade was always referable to complications. Leroux 
found 5,000,000 cells in two cases, between 3,400,000 and 4,800,000 
in five, and 2,200,000 red and 89,000 white in an infant in which the 
disease was complicated by furunculosis. Zappert's four cases showed 
moderate reduction in red cells, 3,900,000 to 4,500,000. Litten has 
recorded two fatal cases arising in the course of pernicious anemia. 
Cabot refers to twelve cases showing no abnormality except eosino- 
philia. 

The leucocytes in uncomplicated cases have been found normal in 
numbers, but often with excess of eosinophile cells. Zappert counted 
630 to 1360 (8 to 19 per cent.) of eosinophiles in four cases. 

The bacteriological examination of the blood during life has thus 
far been negative, although Leredde obtained the staphylococcus albus 



NERVOUS AND MENTAL DISEASES. 387 

from the blood of one case complicated by endocarditis. The blood 
of the cadaver has been found to contain various micro-organisms, 
Triboulet having three positive results in fifteen cases. Bacterio- 
logical studies of the blood and viscera favor the belief in the iden- 
tity of origin of rheumatism and chorea. 

Functional nervous diseases, such as hysteria, neurasthenia, 
hypochondriasis, and tetany, do not give rise to anemia, but 
numerous associated conditions may lead to impoverishment of the 
blood. Cabot and Reinert report uiild grades of chlorotic anemia 
in hysteria and neurasthenia. In neuritis Cabot reports chlorotic 
anemia with marked leucocytosis (16,000 to 28,000) in a febrile case 
in a young subject, while in four of six cases of afebrile alcoholic 
neuritis the leucocytes were slightly increased. 



GRAVES' DISEASE. 

Anemia does not appear to be essentially connected with exoph- 
thalmic goitre, as some cases show nearly normal cells and Hb 
(Oppenheimer). Bramwell reports anemia, grade not stated, in only 
twenty-seven of sixty-four cases. Yet many patients suffer from a 
form of anemia closely resembling chlorosis, which is sometimes 
quite severe. Thus Zappert records two cases with 2,800,000 and 
2,700,000 cells, and 32 "to 30 per cent, of Hb. The writer has 
examined the blood in several such cases, in one of which the 
majority of red cells were distinctly undersized. 

The term ^'thyroid chlorosis'' is applied by Capitan to cases of 
chlorosis associated with enlargement of the thyroid. Referring to 
Hayem's report of twenty-nine goitres among thirty-five chlorotic 
patients, Capitan finds reason to believe that one type of chlorosis is 
referable to thyroid intoxication. Some years ago the writer was 
struck by the peculiar clinical type of chlorotic anemia observed in 
two elderly women suffering from Graves' disease, but has not since 
encountered such cases. 

The leucocytes, in the absence of complications, are normal or 
diminished. Neusser and Cabot have noted relative lymphocytosis. 

Bibliography. 

Nervous and Mental Diseases. 

A-ffl.eck. Edin. Med. Jour., 1900, vol. viii. p. 33. 
Burr. Cited by Cabot. 

Capitan. Compt. Rend. Soc. Biol., 1897, p. 1073 
Capps. Amer. Jour. Med. Sci., vol. cxi. p. 650. 
Daubler. Archiv f. Tropenhvg., 1897, p. 372. 
Fajardo. Cent. f. Bact., Bd. 24, p. 558. 
Howard. Bull. N. Y. State Hosp., I., 1896, p. 139. 
Jelliffe. Bull. N. Y. State Hosp., 1897, p. 397. 
Kuhlmann. BUll. N. Y. State Hosp., 1897, p. 77. 
Langdon, Bamford. Bull. N. Y. State Hosp., 1896, p. 239. 
Leredde. Rev. Mens. Mai. de PEnfanee, 1891. 
Leroux. Mai. de rEnFance (Granclier), IV., p. 819. 
Lewis. Text-book of Mental Diseases, 1889, p. 287. 



388 CONSTITUTIONAL DISEASES. 

Litten. Charite-Annalen, 1884, p. 265. 

McPhail. Jour, of Mental Sci., vol. xxx. pp. 378, 488. 

Oppenhei772er. Deut. med. Woch., 1889, p. 882. 

Pease. Bull. N. Y. State Hosp., 1896, p. 133. 

Roncorini. Archiv di Psychiat., 1894, p. 293. 

Rost. Lancet, 1901, I., p. 66. 

Seppili. Ref. in Jour. Mental Sci., vol. xxxiv. p. 143. 

Smyth. Jour, of Insanitv, 1890, p. 505. 

Somers. Bull. N. Y. State Hosp., 1896, p. 75. 

Spencer. Lancet, 1897, I., p. 32. 

Stanley. Jour, of Hyg., vol. ii. p. 369. 

Steele. x\mer. Jour, of Insanity, vol. xlix. p. 604. 

Sutherland. Jour, of Mental Sci., vol. xxxi. p. 147. 

Trihoulet. These de Paris, 1893, cited by Leroux. 

Winckler. Diss. Bonn, 1891, 



PART V. 

GENERAL DISEASES OF VISCERA. 



CHAPTER XX. 

THE HEMOPOIETIC SYSTEM. 
THE LIVER. 

Relation of its Functions to the Blood. Although the chief 
functions of the liver in the secretion of bile and the elaboration of 
absorbed food products are directly concerned with the maintenance 
of the blood albumins, specific effects of inhibition of these functions 
have not yet been traced in the blood. These effects are doubtless 
seen in the anemia of advanced cirrhosis, but are even then not to 
be distinguished from similar changes in other secondary anemias. 

The function of transforming into bilirubin and removing from the 
system the pigment of disintegrated red cells is being constantly 
exerted in health and disease. When from any cause the excretion 
of this product is obstructed, as in acute yellow atrophy, or the 
demands upon the function are excessive, as in pernicious malaria, 
either hemoglobin or its derivative, bilirubin, accumulates in the 
blood, giving hemoglobinemia or jaundice. In the former case the 
content of the liver in heniatoidin and hemisiderin is an accurate 
index of the grade of blood destruction. There is as yet no proof 
that the liver plays more than a passive part in the destruction of 
blood. 

The embryonal function of the liver as a depot of forming red cells 
is not infrequently retained until after birth, and there is reason to 
believe that the renewal of this function may sometimes give peculiar 
character to the anemia of infants described by v. Jaksch. 

Effects of Bile upon the Blood. A globulicidal action of bile 
was first demonstrated experimentally by Hunefeld (1840), while the 
fact that the biliary acids are the active agents in dissolving red cells 
in jaundice was shown by v. Dusch (1854), and fully established by 
many later studies. V. Dusch not only demonstrated the power of 
bile to dissolve red cells, but claimed that it may also dissolve leuco- 
cytes and even liver cells, a property noted also by Ivywosch, The 
relative globulicidal power of the various salts of biliary acids was 
fully tested by Rywosch, who found that sodium eheuocholato and 



390 GENERAL DISEASES OF VISCERA. 

taurocholate dissolve red cells when in a concentration of 1 to 700, 
or 1 to 600, that ^N'a-cholate is only moderately active at 1 to 200, 
while I^a-glycocholate destroys red cells only when in a solution of 
1 to 50. In the process of solution the red cells first lose their cen- 
tral depression, become variously deformed and finally dissolved, 
leaving no detritus. These changes have been observed only in the 
test-tube, but in the blood of most cases of jaundice the process 
appears to differ from that of other forms of hematocytolysis. 

The resistance of the red cells was found by Limbeck, in all cases 
of jaundice, to be distinctly increased, the cells not dissolving in 
solutions of more than 0.32 per cent. NaCl (normal 0.46 per cent.). 
This change he referred to the destruction of less resistant cells and 
a chemical union of Hb and stroma brought about by the action of 
bile salts. 

Vaquez and Riberre find that the red cells begin to show increased 
resistance on the fourth day of jaundice, which continues until in 
prolonged cases they may fail to dissolve in 0.24 per cent. NaCl. 
They refer this peculiarity to the development of antilysins, which 
are present in the serum, since this serum, added to normal red cells, 
prevents the usual solution by bile. 

An increase in specific gravity of the blood was observed by 
Grawitz, following the injection of bile in animals, and referred by 
him to transudations excited by some specific action on the part of 
the bile. Limbeck also found a relative decrease in volume of the 
serum in obstructive jaundice, as well as a lower percentage of chlo- 
rides. At the same time the volume of the red cells was increased. 

Coagulation is hastened, according to Rywosch, by the presence of 
one part of !Na-chenocholate or taurocholate in 500 of blood, but 
entirely inhibited when the proportion reaches 1 to 250. 

The presence of bile pigments has no deleterious action on the 
blood, although Rywosch found that injections of pure bilirubin, 
while not affecting the blood, produce mild general toxic symptoms. 

Diseases of the Liver. 

Jaundice. In the human subject clinical observations have shown 
that small traces of bile are demonstrable by the greenish-yellow 
color of the serum of very mild cases in which, however, there are 
usually no other changes in the blood. In severe cases, when con- 
siderable quantities of bile are present in the circulation, many of 
the effects observed in the experimental study of jaundice become 
apparent. Any tendency toward concentration which the presence 
of bile may exert is seldom seen clinically, as the majority of severe 
cases of jaundice exhibit some reduction of red cells. This anemia 
is usually referable to pre-existing conditions, but in very severe 
cases actual destruction of red cells may be traced in the dried speci- 
men. A tendency to very rapid crenation and total absence of 
rouleaux have been observed by Grawitz. In the blood of icteric 
infants Hofmeier also noted deficiency in the formation of rouleaux, 
'which, however, are normally less numerous than in the blood of adults. 



THE HEMOPOIETIC SYSTEM. 391 

Evidences of solution of red cells were found by Silberman' in the 
blood of many jaundiced infants. These consisted in the presence 
in the blood of fragments of red cells, and in the liver and spleen of 
many phagocytes inclosing red cells and blood pigment. Many 
other degenerative changes in the red cells were noted, but they 
were not necessarily connected with the jaundice. In severe cases 
examined by the writer, besides the ordinary signs of anemia, there 
were in the blood many very pale and some fragmented red cells, 
and in the viscera deposits of pigment equal to those of pernicious 
malaria. After death reddish acicular crystals (bilirubin ?) were 
sometimes found in the blood. 

A polycythemia referable to the concentrating effect of bile in the 
blood has not often been reported. Yet Becquerel and Rodier 
reported the highest figures in their experience as occurring in a 
case of jaundice, and later observers have abundantly shown that 
well-marked jaundice markedly increases the specific gravity of the 
blood in proportion to the intensity of the jaundice. Grawitz saw 
the gravity rise from 1.050 to 1.061 in a severe case, but does not 
report the number of red cells, Avhile Limbeck and Van Noorden^ 
found the dry residue of the blood to be 22 to 25 per cent, in several 
cases. The gravity of the serum was unaffected by the presence of 
bile in Hammarschlag's twelve cases, but in Limbeck's two cases the 
serum was poor in chlorides. The results of Limbeck's chemical 
analyses indicate that the volume of red cells in jaundice is much 
increased. 

The alkalinity of the blood is in mild cases unchanged (Limbeck), 
but in acute yellow atrophy, de Renzi, using Reale's method, found 
a neutral reaction, while an acid reaction was present in severe catar- 
rhal jaundice and in suppurative hepatitis with jaundice. 

The leucocytes, in simple catarrhal jaundice, have usually been 
found unaffected, but in Grawitz's experience an increase has been 
common and occasionally the leucocytosis has been very marked 
(38,000 to 40,000). It 'is probable that different observers refer to 
different types of cases. 

Cancer of Liver. A large proportion of the carcinomata of the 
liver being primary in the stomach, the anemia of this condition is 
frequently grafted upon that of gastric cancer. The reports of 
Wlajew include one case of secondary pernicious anemia with only 
850,000 red cells, and none showing over 3,000,000, while the leuco- 
cytes ran between 20,000 and 40,000, indicating that this anemia is 
usually severe. The writer's experience at autopsies in these cases 
accords in general with Wlajew's results, as marked emaciation and 
distinct oligemia are usually prominent. The sudden onset of severe 
jaundice in many of the cases suggests the probability that the blood 
may at times suffer concentration. 

Cabot's series of seventeen cases showed well-marked anemia, cells 
under 3,000,000 in only two, while in ten there were over 4,000,000. 

The leucocytes are usually increased in cancer of the liver, but the 
increase is often intermittent. Of nineteen cases Cabot found only six 
with white cells under 10,000, and in none of these six was the exami- 



392 GENERAL DISEASES OF VISCERA. 

nation repeated. Alexander found leucocytosis in two cases, but 
only after repeated examinations. The grade of leucocytosis is 
usually moderate. The fact that when attacking the liver most 
carcinomata are already generalizing, the tendency toward rapid 
growth in the organ, and the early formation of further metastases, 
are some of the factors which account for the frequency of leuco- 
cytosis in hepatic cancer. 

Hypertrophic Cirrhosis with Jaundice. More severe alterations 
of the blood have been observed by Hayem in a case of hypertrophic 
cirrhosis in which the red cells fell below 2,000,000, with increased 
Hb-index and leucocytosis. Severe anemia was also present in two 
cases verified at autopsy and reported by Cabot, but in one only 
2400 leucocytes were found. 

Hanot and Meunier have insisted upon the presence of leucocytosis 
in this form of cirrhosis of liver, finding therein evidence of the 
infectious nature of the disease. They found from 9000 to 21,800 
leucocytes in five cases. Lukachewitch also found 20,000 white 
cells in another case, and Auche reports in three cases intermittent 
leucocytosis, 12,400 to 18,600 cells. IBactena, usmbIIj staphylocoGcus 
pyogenes aureus^ have been found in the blood of ^^ infectious jaun- 
dice/^ sometimes with hypertrophic cirrhosis, by better. 

Cholelithiasis. Considerable interest attaches to the bacteriologi- 
cal examination of the blood in cholelithiasis from the recent dis- 
covery of bacteria in the blood, in several cases, usually in those 
marked by intermittent fever. Staphlycoceus pyogenes aureus has 
been isolated in two cases by ISTetter ; in three cases, once with the 
colon bacillus, by Sittmann ; and in the pus of metastatic abscesses 
by Gilbert and Girode, Brieger, and many others. The pneumococcus 
of Frankel and streptococcus pyogenes were obtained from the blood 
in one case each, both complicated by hepatic abscess, by Canon and 
by Zancarol, while a small bacillus, not identified, was obtained from 
a complicating hepatic abscess and from the ulcerated heart valves, 
by Xetter and Martha. 

The anemia in these cases varies with the previous condition of 
the patient and with a great variety of associated lesions. 

The behavior of the leucocytes is of interest, and may be of value 
in differential diagnosis. Biliary colic may supervene in severe 
attacks without producing any leucocytosis. The onset of jaundice 
is sometimes accompanied by moderate leucocytosis, at other times 
fails to cause any increase of white cells. The difference probably 
depends upon the grade of inflammation excited by the gallstones, 
etc. Here as elsewhere one may expect no leucocytosis with simple 
catarrhal inflammations, but with active suppurative lesions leuco- 
cytosis may reach a pronounced degree (up to 50,000, Cabot). As 
some of these lesions run into abscess of the liver, or pyemia, even 
this high figure is probably not the limit of the leucocytosis. 

Abscess of Liver. The lesion in abscess of the liver may follow 
one of several types : 

1. There may be a large number of small or miliary abscesses 
throughout the liver, filled with creamy or muco-pus. These abscesses 



THE HE3I0P0IETIC SYSTEM. 393 

arise from extension of suppurative cholangitis. The leucocytosis is 
probably a continuation of that observed in cholangitis, but there 
appear to be no direct observations on the blood of this condition. 

2. There may be one or two large cavities filled with creamy 
or stringy pus, and well shut off from the liver tissue by mucous 
or pyogenic membrane. The writer has seen such an abscess run 
its course with little or no increase of white cells in the blood, and 
the leucocytosis is usually slight. In one adult case, the day before 
one-half litre of pus was evacuated at operation, with temperature 
101° F., the blood showed 11,000 leucocytes, 52 per cent, of which 
were mononuclear, 48 per cent, poly nuclear. A previous examination 
had also failed to show distinct leucocytosis. 

3. Large necrotic abscesses with actively suppurating walls are 
practically always attended with marked leucocytosis, up to 50,000, 
but this increase may be distinctly intermittent. 

Acute Yellow Atrophy. Cases recorded by Grawitz and Cabot 
showed 5,150,000, and 5,520,000 red cells, and 12,000 to 16,000 
leucocytes. The exact limits of this disease are as yet imperfectly 
determined, but in three cases seen by the writer there was in each a 
moderate leucocytosis, 15,000 to 21,000. Two of these occurred in 
parturient women at Sloane Maternity Hospital, and showed the 
usual lesions in the liver. In another at Roosevelt Hospital, the 
disease lasted three weeks, and the inner four-fifths of the hepatic 
lobules were necrotic. The red cells were not counted, and the 
absence of rouleaux and the early crenation mentioned by Grawitz 
were not noted. In two cases bacteriological examinations of the 
blood during life, by Sittmann, were negative, but Vincent obtained 
the colon bacillus from the blood of one case during life. 

Echinococcus Cyst of Liver. Hayem classes the echinococcus 
cyst of the liver as one of the conditions leading to leucocytosis and 
excess of fibrin in the blood. Auche in one case ventured to rule 
out the diagnosis of hypertrophic cirrhosis from the absence of an 
excess of leucocytes, the patient showing an echinococcus cyst at 
autopsy, while Wlajew found no change in the blood in a case of 
hydatid cyst of the liver. Neusser, Lepine, Dargein, and Seligman 
all report cases of echinococcus cyst of the liver with leucocytosis 
varying from 15,000 to 28,000 and eosinophile cells from 12 to 57 
per cent. In some instances there was polycythemia. 

Cirrhosis of Liver. In the early stages of the disease, when 
digestion is not much impaired and there are neither jaundice nor 
hemorrhages, the blond is but little altered. Almost invariably the 
Hb is deficient. During the progress of the disease the blood steadily 
deteriorates, giving some of the most typical examples of secondary 
anemia. Abundant cause of the anemia is found in all cases in the 
disturbance of the functions of the liver and stomach, and in other 
cases by the complications of the particular type which the disease 
follows. In slowly progressing cases without special complications 
the blood commonly shows between 3,000,000 to 4,000,0(H^ cells, 55 
to 75 per cent, of Hb, and little or no leucocytosis. 

In Haan's twenty cases the Hb ran between 60 and 110 per oont., 



394 GENERAL DISEASES OF VISCERA, 

while the Hb-iiidex was uniformly high, above normal in eleven 
cases. 

The ordinary progress of the anemia is perhaps most affected by 
profuse hemorrhages, after which the blood shows the usual reduction 
of red cells and Hb, with nucleated red cells and leucocytosis. Single 
hemorrhages may occur in subjects which are only slightly anemic, 
and the blood is then rapidly restored. In the later stages of the 
disease single or repeated hemorrhages if not at once fatal often lead 
to very grave secondary pernicious anemia. 

Ascites, although draining the blood of much albumin, is commonly 
found with lesser grades of chlorotic anemia. It is not uncommon 
to find, in well-advanced cases requiring paracentesis, 4,500,000 to 
5,000,000 red cells and Hb above 65 per cent. Grawitz believes 
that the ascitic transudate leads to some concentration of the blood 
and the masking of anemia. Such a condition is strongly suggested 
at times by the disproportion between the anemic appearance of the 
patient and the slight changes demonstrable in the blood. The effects 
of paracentesis vary. Limbeck observed a case of Laennec's cirrhosis, 
with extreme ascites, in which the removal of eighteen litres of fluid 
raised the red cells after twenty-four hours from 3,280,000 to 5,160,- 
000. Three days later they fell to 3,540,000. Osterspey noted the 
same result after several tappings of the same patient. On the other 
hand, Grawitz saw the red cells fall from 4,700,000 to 4,300,000 
shortly after tapping, but the first examination came three days 
before the operation. The results of tapping may very well vary 
with the immediate effects upon the circulation, with the state of the 
kidneys, and with the reappearance of the ascites. 

Jaundice, if mild, has no demonstrable influence on the blood of 
cirrhosis ; nor do the ordinary chronic forms of moderately severe 
jaundice appear to be accompanied by any special alteration in the 
blood except a tendency toward leucocytosis. 

In most of the jaundiced cases reported by Hayem, Cabot, and 
others there was a moderate leucocytosis, reaching 20,000 or more. 
Haan, in nine cases with jaundice, found the leucocytes to vary be- 
tween 2100 and 20,900, and in eleven cases without jaundice between 
16,600 and 38,000. Severe jaundice usually occurs in advanced and 
anemic cases, or in the hypertrophic forms. The ordinary cirrhotic 
process in the liver is unaccompanied by leucocytosis, which, how- 
ever, may frequently arise from many complications or accidental 
causes. Thus Hayem, Osterspey, Cabot, and others found no leucocy- 
tosis except from complications, but Grawitz, Rosenstein, and Wlajew 
refer to cases with moderate leucocytosis without giving details. 

DISEASES OF GASTRO-INTESTINAL TRACT. 
Esophagus. 

Stenosis of the esophagus, when extreme, by diminishing the 
quantity of fluid ingested, has been shown to lead to marked concen- 
tration of the blood. Van jN'oorden^ refers to two cases of cancer of 



THE HE3I0P0IETIC SYSTEM. 395 



the esophagus in which the dry residue of the blood reached 26.5 
and 27.3 per cent, (normal 21 to 22 per cent.). When to this condi- 
tion of concentration is added the cachexia which belongs to car- 
cinoma and to starvation, a marked degree of oligemia may result, 
approaching that of pernicious anemia. A distinctly reduced 
quantity of blood was noted at autopsy in one of two cases of 
epithelioma of the esophagus, observed by the writer at Roosevelt 
Hospital, while in the other, in which death resulted from pulmonary 
extension and pneumonia, the stenosis was not extreme. These 
same factors may perhaps be responsible for some relative increase 
in the numbers of red cells which has been observed in a few cases. 
The red cells in reported cases have been above normal, or very 
slightly reduced, as in other forms of cancer, or greatly reduced, as 
in the severe anemia of cancerous cachexia. 

Comparing his own results in a single case with those of Escherich, 
Pee, and Osterspey, Rieder concluded that the cachexia of epithelioma 
of the esophagus differs from that of carcinoma in other regions in 
the absence of leucocytosis. Reinbach also reported two cases with 
relative lymphocytosis. Cabot and Hoffman, however, report several 
cases with moderate leucocytosis. In the writer's cases there was 
antemortem increase of white cells. There has been no attempt to 
refer these varying results to the special causes of leucocytosis to 
which they are probably due. 

Diseases of the Stomach. 

General Considerations. Since the blood depends for its supply 
of albumins chiefly upon the functional activity of the stomach there 
is an intimate relation between the condition of the blood and the 
activity of digestion and absorption in this organ. 

1. Transitory functional disturbances of the stomach usually fail 
to notably alter the blood, but persistent vomiting with hyperacidity 
has resulted in distinct concentration of the blood and reduction of 
chlorides both in blood and urine. 

2. While total withdrawal of food for a short period causes com- 
paratively little change in the blood, a long-continued failure of 
digestion or absorption is one of the most efficient causes of anemia. 
It has already been shown that organic lesions of the stomach are 
prominent among the pathological findings in cases of pernicious 
anemia, including chronic gastritis, atrophy of gastric mucosa, stenosis 
of the pylorus, and cancer. All the lesser grades and types of anemia 
are observed, with even greater frequency, to be associated with gas- 
tric lesions, while the anemia of marasmic infants is doubtless largely 
owing to failure of digestion and absorption, without oroanic lesion 
in the stomach. Meynert's theory of chlorosis further illustrates the 
well-founded belief in the importance of normal digestion in main- 
taining the normal condition of the blood. 

3. The stomach is a frequent site of loss (^f blood bv hemorrhage. 
If, as is indicated by the studies of (iuincke and of Dettwyler and 
Silberman,^ anemia or hemoglobinemia are strong jn'cdisposing causes 



396 GENERAL DISEASES OF VISCERA. 

of ulceration of the stomach and dnodenum, there is in the interac- 
tion of these two conditions a " circukis vitiosus" which readily 
explains their freqnent association in the same subject, and the very 
severe grades of anemia which thereby result. Smaller and more 
frequent bleedings also greatly aggravate the anemia which accom- 
panies ulcerating carcinoma. 

4. Much has been written about the effects of gastrointestinal 
toxemia, but the chief source of autotoxic agents is without doubt 
the intestine. 

The Blood in Hunger. — Muhlman has contributed an exhaustive critique of 
the extensive literature on the blood in hunger, drawing the following general 
conclusions : The specific gravity is uniformly increased. The volume of 
blood diminished 17.5 per cent, after moderate periods of abstinence from 
food, and as much as 37 per cent, after extreme periods. The red cells are not 
much changed, although sometimes slightly increased, until 15 per cent, of 
the body weight is lost, after which they diminish steadily until death, A 
maximum loss of 32 per cent, has been observed on the twenty-eighth day. 
Some observers, however, found polycythemia at all periods. The leucocytes 
fall 20 per cent, until 20 per cent, of the body weight is lost, after which they 
tend to increase, and are usually found above normal. The lymphocytes 
diminish steadily from the first, while the polynuclear cells diminish at first, 
but later reach normal numbers. 

Grawitz finds that hunger in man tends to increase the Hb and red cells. A 
deficiency of albumins and fats in the blood reduces the albumins of the 
serum, before any change in Hb is observed, but if this deficiency is continued 
anemia with loss of Hb follows. 

Special Diseases of the Stomach. 

Acute Gastritis, Dyspepsia, Hyperacidity. These conditions, 
if not prolonged, have no tendency to produce anemia. If vomiting 
is excessive the cells and Hb may be increased. The leucocytes are 
sometimes increased, sometimes normal or diminished. Their num- 
bers may indicate the intensity but not the etiology of the inflam- 
mation. 

Chronic Gastritis. Chronic gastritis may be tolerated for long 
periods without leading to any marked anemia, as the writer has 
often observed in cases addicted to alcohol. When the patients be- 
come disabled anemia of the secondary chlorotic type is usually found 
to be associated with loss of flesh. The leucocytes are low and 
lymphocytes usually prevail (Blindeman, Cabot, Hoffman). Diges- 
tion leucocytosis may be diminished and is sometimes absent, as in 
cancer. 

Associated with chronic gastritis and fibrous stricture of the pylorus, 
the writer has twice observed slowly progressive anemia lasting four 
and five years. The changes in the blood were first chlorotic, later 
intermediate, and, finally, those of pernicious anemia without many 
megaloblasts in the blood, but with typical changes in the marrow. 
Much more acute and typical cases of pernicious anemia have been 
referred to chronic gastritis (Pepper, Stengel). 

Dilatation of Stomach. In cases of gastrectasis from chronic 
gastritis or stenosis of pylorus the blood does not differ from that of 
simple uncomplicated chronic gastritis. Although the patients become 



THE HEMOPOIETIC SYSTEM. 397 

cachectic and lose flesh, the blood usually fails to show corresponding 
anemia. In the cases reported by Reinert, Cabot, Blindeman, and 
others the red cells and Hb were normal or increased or but slightly 
reduced. It is generally agreed that oligemia exists in these cases, 
but its origin is not clear, and it is by no means evident that the 
concentration of the blood is affected, as Kussmaul suggests, by 
excessive vomiting. Defective absorption is probably a more 
important factor. 

The Blood in Gastro -intestinal Diseases of Infants. Acute 
gastro-enteritis occurring in healthy infants usually tends to concen- 
trate the blood, but these effects are demonstrable only in severe 
cases. Felsenthal and Bernhard, in twenty cases, found uniform 
polycythemia reaching 7,500,000 cells, and usually moderate leuco- 
cytosis. Hock and Schlesinger found a moderate increase in specific 
gravity in very severe but not in ordinary cases. On the other 
hand, in an anemic rachitic infant with diarrhea the Hb fell in one 
week from 80 to 60 per cent., indicating that a pre-existing anemia 
may be aggravated by such attacks. 

In chronic gastro-enteritis there may be progressive anemia and 
emaciation, as in Hayem^s case, in which after two months the red 
cells numbered only 685,000, leucocytes 18,910. On the other hand, 
Monti and Berggrun report a case lasting six weeks in which the 
blood of the emaciated subject showed 4,100,000 red cells and 65 
per cent, of Hb. In most of FelsenthaPs cases the Hb rose above 
65 per cent, only when there was marked polycythemia, while 
moderate leucocytosis was the rule. 

The grade of anemia observed in marasmic infants with mild gas- 
tro-intestinal disturbance is very variable, and its different phases 
illustrate all the stages of secondary anemia. It is usually charac- 
terized by relative or absolute lymphocytosis. 

The behavior of the leucocytes varies greatly, being influenced by 
the age of the patient, the type of the disease, and the occurrence of 
complications, such as vomiting and severe diarrhea, which concen- 
trate the blood, and hemorrhage with anemia. 

Japha, in a series of miscellaneous hospital patients under one 
year of age, found the leucocytes to vary greatly, while the average 
was 13,500, of which 42 per cent, were polynuclear cells. 

In dyspepsia, simple gastro-enteritis (dyspeptic diarrhea), and 
infantile atrophy he found no changes in the proportions of leuco- 
cytes and only the ordinary variations in their numbers. 

In follicular enteritis and cholera infantum with distinct anatomi- 
cal lesions of the intestine there was usually moderate or considerable 
polynuclear leucocytosis. Similar results have been obtained by 
Gundobin, d'Orlandi, and Knox and Warfield. Most of these ob- 
servers inchide in their series cases of pronounced ulcerative colitis, 
in which the usual polynuclear leucocytosis was often marked. 

On the other hand, several observers have encountered distinct, 
absolute, and slight or marked relative lymphocytosis in the milder 
intestinal disorders of infants. 

Fischl found considerable leucocytosis with 60 per cent, or more 



398 GENERAL DISEASES OF VISCERA. 

of lymphocytes to be the rale in his cases. Hock and Schlesinger^ 
in the above-mentioned case, found 38,000 leucocytes, the majority 
of which were large lymphocytes. Stengel and White, in an acute 
case with blood-streaked mucous stools, counted 70 per cent, of 
lymphocytes among 28,000 cells. In two cases of cholera infantum 
reported by Weiss the lymphocytosis approached the grade of 
lymphatic leukemia. 

Ulcer of Stomach. The state of the blood in ulcer of the stomach 
is extremely variable, and it is not always evident what conclusions 
to draw from the results of its examination. From the very numerous 
cases reported in greater or less detail by Leichtenstern, Laache, 
Haeberlin, Oppenheimer, F. Miiller, Schneider, Reinert, Osterspey, 
Cabot, Rochemont, and others, as well as from the writer's own 
observation, these changes seem to fall in some rather distinct classes. 

1 . Some cases appear to have suffered no permanent change in the 
composition of the blood, but from their anemic appearance it is 
probable that the total volume of blood has been reduced, without 
marked alteration in its quality 

Most of these patients have never sustained a large hemorrhage, or a former 
loss of blood has been replaced through the active regeneration which is often 
seen in this condition. Miiller and Oppenheimer have referred especially to 
such cases, while Grawitz demonstrated in one patient that the blood was de- 
cidedly hydremic, the dry residue of the serum being only 8.56 per cent., 
while that of the whole blood was 19.75 per cent., and the red cells numbered 
4,340,000. This patient was recovering from more severe anemia and still 
gave anemic heart murmurs. A single chemical analysis, while most im- 
portant, cannot with certainty be applied to all these patients, however, and 
several of Oppenheimer's reports indicate that the blood may be entirely nor- 
mal in some cases of gastric ulcer. It does not seem probable that vomiting 
or other causes of concentration of the blood are important factors in the 
majority of these cases. 

2. The usual state of the blood is one of marked secondary chlorotic 
anemia, with little or no leiicocytosis, the presence of which depends 
largely upon the manner of feeding. While the regeneration of the 
blood after hemorrhage is often very rapid, it is seldom complete 
while the patient remains in the hospital, and there seems to be some 
influence, possibly found in a diminished digestive power in the 
stomach, which causes the anemia to persist. 

The writer followed one male patient for five years after a dangerous hemor- 
rhage, but although all local and other general symptoms had disappeared, the 
blood never showed more than 75 per cent, of Hb. 

3. The bleedings of ulcer of the stomach furnish some of the most 
remarkable examples of post-hemorrhagic anemia, the characters of 
which have been described. Surviving patients seldom show less 
than 1,000,000 cells, but from this point may improve rapidly, with 
low Hb-index, normoblasts, and leucocytosis. Cases with cells under 
3,000,000 have usually suffered from hemorrhages, which if fre- 
quently repeated may lead to grave anemia with rising Hb-index 
and increasing diameters of red cells. The lowest specific gravity of 
the blood (1023) encountered by Grawitz in his studies was in a case 
of gastric ulcer with 400,000 red cells. 



THE HEMOPOIETIC SYSTEM. 399 

Leucocytes. Leucocytosis of moderate grade follows hemorrhage 
or local inflammation. In one case with marked leucocytosis the 
writer found two perforated ulcers, one opening into a large cavity 
in the liver, the other connected with an abscess of the liver. In 
quiescent periods, with rectal feeding, there is usually hypoleucocy- 
tosis, while the change to feeding by the stomach may excite con- 
siderable digestion leucocytosis, as in Cabot's case, in which the first 
meal raised the white cells from 4000 to 15,000. These features 
may be of diagnostic value when cancer is suspected, but should be 
interpreted with caution. Digestion leucocytosis has been absent in 
ten cases of ulcer reported by Hoffman, Hassman, and Schneyer. 
In three of these there was stenosis of the pylorus. 

Cancer of Stomach. The usual course of the anemia of malig- 
nant neoplasms is varied by the peculiar conditions connected with a 
tumor of this organ, and by the extent and character of the new 
growth. In the reports of some 200 cases to be found in the litera- 
ture there has been no systematic attempt to classify the types of 
anemia with reference to the character of the tumor, and while it 
appears by no means certain that such a classification would be of 
clinical value, there are, nevertheless, certain features of the growth 
and complications of these tumors which chiefly determine the state 
of the blood. 

1. Some caTicers of the stomach exist for considerable periods without 
leading to marked impoverishment of the blood, and there is no neces- 
sary cause of anemia in the early stages of most of those which do 
not bleed, ulcerate, or contract the pylorus. When chronic gastritis 
or ulcer precede cancer, the pre-existing anemia suffers at the time 
no appreciable change. Accordingly, it is a common experience to 
find in the blood at this time no distinct indication of the presence 
of a malignant tumor in the body. At this time the general symp- 
toms are more reliable diagnostic signs than is the state of the blood. 
Moreover, if vomiting is a prominent early symptom, an initial 
anemia may be masked by temporary concentration of the blood. 
Cabot reports over 4,000,000 red cells in 64, and over 5,000,000 in 
25, out of 114 cases. Price-Jones followed a case which at first 
showed 6,270,000 red cells, 50 per cent. Hb, but one month later 
3,750,000 and about the same amount of Hb, 48 per cent. 

The first sign of affection of the blood is seen in the falling Hb, 
which has been found considerably reduced in many of the cases with 
normal or nearly normal red cells. Mouisset and Tolot, and Labbe 
find that the combination of a low Hb-index, excess of polynuclear 
cells, and absence of fever is a diagnostic sign seldom lacking in early 
gastric carcinoma, and fails only in some very early cases or when 
there is some sudden loss of red cells. Yet none of these rules is at 
all constant. 

2. In the majority of cases of gastric cancer the red cells arc reduced 
in number, the Hb is deficient, and the blood shows the changes of 
secondary chlorotic anemia. The reduction of cells is sometimes 
remarkably slight, but the Hb usually suffers first and most severely. 
When distinct cachexia is present, both red cells and Hb are nearly 



400 GENERAL DISEASES OF VISCERA. 

always reduced, unless there is active vomiting. Poikilocytosis 
appears in the more chronic and severe cases. Nucleated red cells 
are usually seen in small numbers. Sometimes they are present 
when the anemia is very slight. Jez found them so common in 
cancer and so rare in ulcer as to furnish diagnostic evidence between 
these conditions. 

The Hh-index is commonly subnormal, but not so low as in chlo- 
rosis. Osier and McCrae, however, found an index of 0.63 in fifty- 
two cases, which is nearly as low as that of chlorosis. In Price- 
Jones' cases the Hb-index was either high or low, but did not vary 
much during considerable periods of observation. The Hb is very 
much less likely to increase when once low, while it does increase, 
frequently and rapidly, in simple ulcer (Blindeman). 

The conditions which tend to develop severe anemia in gastric 
cancer are chiefly hemorrhage, ulceration, and metastasis. Diffuse 
growths and annular pyloric tumors have less effect upon the blood. 

3. A moderate proportion of cancers of the stomach pursue a course 
lohich clearly resembles that of pernicious anemia. Without very 
marked gastric symptoms and with no demonstrable tumor the blood 
becomes excessively anemic, the red cells falling to a low figure, 
usually about 1,500,0)0 to 1,000,000, megalocytes are abundant, and 
nucleated red cells, some of which may be of large size, make their 
appearance. 

The type of carcinoma found in these cases varies. Sometimes there is a 
small tumor of the stomach wall with moderate neighboring metastasis, sug- 
gesting the development of cancer in an old round ulcer. Sailer, Sadler, and 
Menetrier report such cases, and the writer has seen two others at autopsy. 
Usually the tumor is of considerable size and ulcerating, as in another case 
reported by the writer. It is not probable, however, that the grave form of 
anemia is necessarily associated with any particular forms of cancer, as both 
the above types may be seen without extreme anemia. Menetrier and 
Aubertin discuss the possibility that in these cases the tumor may develop 
unusually active hemolytic agents. 

In the diagnosis of this type of gastric cancer from pernicious 
anemia one is usually aided in the examination of the blood by the 
following features : 

(a) The majority of megalocytes do not show an excess of Hb, 
which is distinctly more deficient than in pernicious anemia. 

(h) Megaloblasts are rare, and nucleated red cells, if present, are 
mostly of normal size or but slightly larger than normal. 

(c) There is usually polynuclear leucocytosis in advanced carci- 
noma of stomach. 

The leucocytosis may fail and a few megaloblasts may be present, 
but the writer has been unable to find a case of grave anemia in 
cancer of the stomach in which the general deficiency of Hb was not 
marked. 

Henry calls attention to the fact that in cancer the cachexia exceeds 
the oligocythemia, while in pernicious anemia the opposite relation 
holds, but the anemic type of gastric cancer has in several reported 
cases reduced the red cells below 1,500,000, the limit noted in his 
experience. In his statement that at death pernicious anemia leaves 



THE HEMOPOIETIC SYSTEM. 401 

fewer red cells (usually below 1,000,000) than gastric cancer (usually 
above 1,000,000) most observers will concur. 

Leucocytosis in Gastric Cancer. Poljnuclear leucocytosis is present 
in the majority of cases, but not in all. In the early stages of the 
disease^ when diagnoses are difficult, leucocytosis is frequently absent^ 
and if we exclude the slight increases the majority of early cases fail 
to show leucocytosis. This fact probably depends on the usual 
absence of any cause of leucocytosis which the tumor itself does not 
furnish. Without much regard to the position of the tumor or the 
rapidity of growth, leucocytosis makes its appearance as a result of 
ulceration, exudative inflammation about the tumor, hemorrhage^ 
metastasis, and anemia. In the writer'js experience these causes are 
most active in the order named. A single examination of the blood 
is, however, quite insufficient to exclude the occurrence of the leuco- 
cytosis which is now under consideration. The leucocytosis of 
secondary anemia is often intermittent, according to the process 
which it follows, and its detection may require repeated examinations. 

The grade of leucocytosis is usually not high, but since in low 
states of nutrition the leucocytes are usually low, the presence of 
10,000 leucocytes has here more significance than in states of health. 
The majority of advanced cases show between 10,000 and 20,000 
white cells. Extreme leucocytosis has usually been found to result 
from complicating inflammation, extensive ulceration, or numerous 
metastases. It is said that some cases may pursue their course 
entirely without leucocytosis. 

When the total numbers are distinctly increased the proportion of 
polynuclear leucocytes is usually high. This fact is especially 
apparent in the cases reported by Osier and McCrae. Eosinophile 
cells, how^ever, are nearly always present, and sometimes their num- 
bers and proportions are considerably increased (5 to 6 per cent.). 
It is of interest to note that Labbe has found many eosinophile cells 
in the tissue in and about an excised cancer of the stomach as well 
as in the adjoining lymph nodes. 

Digestion Leucocytosis in Cancer of Stomach. R. Miiller, in 1890, 
first called attention to the absence of digestion leucocytosis in cancer 
of the stomach, and this fact has since been abundantly verified by 
the reports of Schneyer, Hoffman, Hartung, Capps, Sailer, Cabot, 
Hassman, and Jez. 

Miiller, Schneyer, Jez, and Hartung found no digestion leucocytosis in their 
41 cases, while in simple ulcer it was always present, except in one case of 
hematemesis. Hartung found it present in four cases of cancer of other 
organs. Capps and Cabot report digestion leucocytosis of 3270 to 3850 cells in 
3 of 37 cases, while it was present in only 5 of 10 cases of chronic gastritis, 
and in one case of fibrous stricture of pylorus. More recently Hoffman, find- 
ing digestion leucocytosis in 3 of 24 cases of cancer, but in only 2 of 9 cases of 
ulcer of stomach, and in only 2 of 11 cases of anacidity from other causes, 
denies any great diagnostic value in the test. Hassman and Schneyer also 
found no digestion leucocytosis in three cases of ulcer with pyloric stenosis, 
while Sailer found no digestion leucocytosis in one case of tuberculous cachexia, 
and in two cases with pre-existing inflammatory leucocytosis. Osier and 
McCrea demonstrated an increase of 33 per cent, of leucocytes following 
digestion in 10 of 22 cases of gastric cancer. 

26 



402 GENERAL DISEASES OF VISCERA. 

The above studies showing that digestion leucocytosis is absent 
when the stomach fails either to digest or absorb with considerable 
activity, conditions which usaally but not necessarily accompany 
carcinoma, but which may also be found in simple ulcer, chronic gas- 
tritis, stenosis of pylorus, gastroptosis, anacidity, tuberculosis, etc., 
it appears that this test can hold only a very subordinate position in 
the diagnosis of cancer of the stomach. 

Duodenal ulcer closely resembles gastric ulcer in its effects upon 
the blood. 

Diseases of the Intestine. 

The blood is very closely dependent upon the absorptive and excre- 
tory functions of the intestine both for its transient variations in con- 
centration and its more permanent supply of albumins. So marked 
and prompt is the response of the blood to these changing conditions 
that no examination of the blood requiring accurate calculation should 
be made without full regard to the condition of the gastro-intestinal 
tract. The writer has repeatedly seen an attack of typhoid fever 
completely obliterate the signs of a moderate chlorosis ; and has pre- 
viously referred to the remarkable transformation of the blood 
observed when, at Montauk, in 1898, typhoid fever developed in 
subjects of malarial cachexia. Of the two main intestinal functions 
the blood responds much more promptly to excessive excretion than 
to increased absorption. 

Effects of Absorption. During the early stages of digestion of 
solid food the red cells tend to increase, owing to the discharge of a 
considerable bulk of digestive fluids (Buntzen, Sorenson, Leichten- 
stern). With largely fluid diet, on the other hand, the absorption of 
fluids may tend from the first to diminish the red cells, so that their 
lowest proportion is found about four hours after meals. At the same 
time coagulation is slower (Vierordt, Leichtenstern). The increased 
flow of lymph doubtless contributes to this result. With proper diet 
in healthy adults these processes usually fail to cause important varia- 
tions in the red cells and Hb of the blood, and even when the quan- 
tity of fluid in the food is excessive or extremely deficient the demon- 
strable effects are slight and very transient. Leichtenstern could 
detect no change in the blood of a patient who drank 21.5 litres of 
water during three days, and Schmaltz found only a slight reduction 
in gravity (1.059 to 1.057) forty-five minutes after the ingestion of 
4 litres of physiological salt solution. The ingestion of very large 
quantities of fluid can dilute the blood only to a slight degree, beyond 
which the activity of the kidneys is sufficient to carry off all excess 
and keep the gravity of the blood within somewhat narrow limits. 

Depletion of the blood by limited ingestion of fluids and especially 
by watery exudates leads, on the other hand, to very prompt and con- 
siderable concentration of the Mood. Numerous clinical illustrations 
of this fact have already been considered as arising from disorders of 
the stomach, but the more extreme examples are connected with the 
use of purges and with diseases of the intestine, especially those 
attended with active diarrhea. 



THE HEMOPOIETIC SYSTE3L 403 

Effect of Purges upon the Blood. It was held by Poisseuil in 
1839 that when salines are administered in greater concentration 
than that of the blood serum, the la^ys of osmosis determine the 
passage of fluids from the blood into the intestine. It has since been 
shown that with many laxatives other factors lead to the same result, 
especially the increased intestinal secretion and the failure of absorp- 
tion. 

Brouardel first demonstrated an increase of blood cells following purgation, 
finding that with severe diarrhea the red cells might rise as much as 1,456,000 
per c.mm. The leucocytes were at the same time increased, maximum 5880, 
but apparently for different reasons and not in proportion to the red cells. 
Later, Hay found an increase of nearly 2,000,000 red cells within one and a 
half hours after the administration of a large dose of Glauber's salt. The 
increase began in a few minutes, and the normal condition was restored in 
about four hours. The effects were more marked the more concentrated 
the solution ; but after a certain concentration of blood had been reached, no 
further effects could be induced and no purgation followed the continued ad- 
ministration of the saline. Likewise Grawitz found the administration of 15 
grains of Epsom salt in 50 c.c. water to raise the gravity of the blood, begin- 
ning in five minutes and reaching a maximum increase, from 1.0591 to 1.0539, 
in forty-two minutes, after which there was a steady decline. Common salt 
was even more active, 15 grains in a little water raising the gravity of the 
blood from 1.050 to 1.060 within twenty minutes. The effects of such salines 
he found were largely nullified when the stomach and intestines contained 
much food. 

Colitis (Dysentery). Acute colitis of croupous or ulcerative type 
usually causes some concentration of the blood and is attended with 
considerable leucocytosis. After the acute febrile period, if the 
patient survives, anemia replaces the oligemia and the leucocytosis 
becomes intermittent. Yet the writer has seen excessively emaciated 
cases of acute amebic colitis die, without fever, and without marked 
reduction in the proportion of red cells. 

Chronic ulcerative colitis, when attended by much purulent exudate 
and numerous hemorrhages, may lead to extreme anemia of secondary 
chlorotic or pernicious type. Leucocytosis if present is intermittent. 

Catarrhal colitis has little effect upon the blood, tending by deple- 
tion to raise the proportion of red cells. There is usually no leuco- 
cytosis. 

Simple acute diarrhea causes a slight transitory increase of cells 
and Hb. 

Cholera. The most extreme grades of concentration of the blood 
are seen in those cases of Asiatic cholera which die in the algid stage, 
and in which the system has been excessively depleted by prolonged 
diarrhea. The diminution in the quantity of blood may even be 
plainly visible to the naked eye, in the scanty hemorrhage which 
follows section of an artery (Dieffenbach). 

The principal changes in the blood of cholera are fully set forth in 
the first systematic study of the subject by Schmidt, who in speci- 
mens obtained by venesection found the specific gravity of the whole 
blood raised from 1.050 or 1.059 to 1.065 or 1.073, of the serum 
from 1.029 to 1.047. Even the red cells were found to suffer a 
marked loss of water, their gravity rising from 1.088 to 1.102. 



404 GENERAL DISEASES OF VISCERA. 

Moreover, while the increase in density of the blood and serum was 
not uniform nor in all cases well marked, the changes in the red cells 
Avere pronounced and invariable. Schmidt^s analyses were not made 
in the most extreme cases, however ; and the relation between the 
gravities of the blood, the cells, and the serum indicates that the 
relative quantity of serum had remained about normal. Other and 
older observers (Thomson) had previously noted a gravity of the 
serum as high as 1.057, indicating that the serum had begun to suffer 
disproportionately in bulk, and that a true oligoplasmia existed. 

Schmidt and Biernacki added to the knowledge of the subject the 
fact that all chemical constituents are increased in rather uniform 
proportion except the sodium chloride, which seems to transude in 
the stools in excessive quantity. Biernacki, finally, has shown that 
these excessive grades of depletion of the blood do not exist unless 
the tissues are themselves seriously drained of fluids and can no longer 
supply water to the blood. 

The coagulability was found by Hayem and Winter to be sometimes 
normal, but often, in the stage of reaction, much increased. They 
found a much diminished capacity of the blood to absorb oxygen. 

The alkalescence of the blood in cholera was regarded by the older 
observers as extremely deficient, and Cantani in 1884 claimed to 
have demonstrated a rapid decrease of alkalinity, a neutral reaction 
during the algid stage, and even an acid reaction before death. This 
change he referred to excess of CO.^, and he recommended treatment 
by alkalits. Biernacki refers the diminished alkalinity to loss of 
sodium. Hayem and Winter examined twelve specimens of blood 
during the stage of collapse, finding four of them neutral or slightly 
alkaline, and eight slightly acid. The reaction has not been deter- 
mined by more recent methods. 

The red cells are markedly increased in nearly all cases. In one 
instance they rose to 7,662,000 within twenty-four hours, the patient 
finally recovering. Usually the red cells rise to 6,500,000 or 7,500,000, 
and this excess is usually but not always proportionate to the 
other evidences of concentration. One case showed a maximum of 
over 8,000,000 red cells, while another gave only 3,193,000 during 
the stage of reaction. Beginning concentration has been noted as 
early as the third hour. Biernacki attributes to the thickening of 
the blood and especially to the depletion of tissues considerable 
importance in the pathogenesis of symptoms, but found very severe 
symptoms in patients not showing much diarrhea. Eogers found 
uniform polycythemia reaching over 8,000,000 in two fatal cases, 
but could not detect any relation between the concentration of the 
blood and the ultimate course of the disease. 

Morphological changes in the red cells have not been noted by most 
observers, but Nicati reports that in hemorrhagic and jaundiced cases 
there are many shadows of dissolving red cells, and often pigmented 
leucocytes, to be seen, especially in the stage of reaction. 

Leucocjrtosis is practically constant in all marked cases. Biernacki 
found 21,250 cells in one mild case suffering chiefly from diarrhea, 
but only 4375 in another very similar case. Eight cases showing 



THE HEMOPOIETIC SYSTEM. 405 

in the algid stage very high leucocjtosis, 40,000 to 60,000, were 
fatal. Some cases with more moderate leucocytosis (20,000 to 30,000) 
were also fatal, but less rapidly. In the stage of reaction the leuco- 
cytes are usually lower, but some fatal cases show a persistent or 
increasing leucocytosis in this stage. The increase of leucocytes is 
relatively much greater than that of the red cells. It has been noted 
as early as the twelfth hour, and may persist as long as six days. 
The polynuclear cells are in great excess, and eosinophiles are usually 
absent. Eogers observed leucocytosis in proportion to the severity 
of the disease. He describes as characteristic an increase in the 
number and proportion of large mononuclear cells, especially in fatal 
cases. When these cells exceeded 10 per cent., the patient usually 
died. 

Bacteriology of the Blood. The comma bacillus has apparently not 
been found in the blood during life. After death it was recovered 
from the heart's blood in a small proportion of forty-eight cases 
examined by Lesage and Macaigne, and in four of eleven cases 
examined eight to twenty-four hours after death by Rokowsky. 
Wlajew failed to obtain positive results from the heart's blood in 
several cases, and one specimen of blood, drawn during life,was sterile 
and non-pathogenic to animals. Diatroptoff also found three sterile 
specimens of heart's blood. 

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Alexander. These de Paris, 1887. 
Auche. Gaz. hebdom., 1897, p. 459. 
Becquerel, Rodier. Loc. cit., p. 103. 
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Brouardel. L 'Union Med., 1876, T. 22, p. 405. 
Canon. Deut. med. Woch., 1893, p. 1038. 
Cantani. Cent. f. med. Wissen., 1884, p. 785. 
Capps. Boston Med. and Surg. Jour., vol. cxxxvii. p. 468. 
Dargein. Compt. Rend. Soc. Biol., 1901, p. 969. 
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Diejfenbach. Cited by Lukianow, Grundz. allg. Path. d. Gefass-syst., Leipzig, 
1894, p. 221. 

V. Dusch. Inaug. Diss. Leipzig, 1854, 

Escherich. Berl. klin. Woch., 1884, p. 145. 

Ewing. Trans. N. Y. Path. Soc, 1897-8, p. 136. 

Felsenthal, Bernhard. Archiv f. Kinderheilk., Bd. 17, p. 333. 

Fischl. Zeit. f. Heilk., Bd. 13, p. 277; ibid., 1892. 

Gilbert, Girode. Semaine Med., 1890, p. 481. 

Grawitz. Berl. klin. Woch., 1895, No. 48. 

Gundobin. Jahrb. f. Kinderheilk., 1893. 

Haan. Archiv f. Verdauungskrank., 1898, Bd. 4. 

Haeberlin. Miinch. med. Woch., 1888, No. 22. 

Hanoi, Meunier. Compt. Rend. Soc. Biol., 1895, p. 49. 

Hartung. Wien. klin. Woch., 1895, p. 697. 

Hassman. Wien. klin. Woch., 1896, p. 314. 

Hay. Jour, of Anat. and Physiol., 1882, p. 430. 

Hay em. Gaz. hebdom., 1889, p. 726. 

Hayem, Winter. Gaz. hebdom., 1885, pp. 118-138. 

Henry. Archiv f. Verdauungskrank., 1898, p. 1. 



406 GENERAL DISEASES OF VISCERA. 

Hock, Schlesinger. Beitrage zur Kinderheilk., 1892. 

Hoffman. Zeit f. klin. :Med., Bd. 33, p. 460. 

Hoffmeier. Die Gelbsucht d. Xeugeborenen, Stuttgart, 1882. 

Hunefeld. Der Chem. tierisch. Organis., Leipzig, 1840. Cited by Rywosch. 

Japha. Jahrb. f. Kinderheilk., 1901, p. 179. 

Jez. Wien. med. Woch., 1898, p. 633. 

Knox, Warfield. Johns Hopk. Bull., 13, p. 167. 

Kussmaul. Beii. klin. Woch., 1872, p. 37. 

Laache. Die Anaemie, 1883. 

Labhe. Bull. Soc. Anat. Paris, 1899, p. 85. 

Leichtenstern. Untersuch. u. d. Hb-gehalt. des Blut., 1878 

Lepine. Compt. Rend. Soc. Biol., 1902, p. 285. 

Lesage, Macaigne. Annal. Institut Pasteur, 1893, p. 17. 

Lukachewitch. Cited by Auche. 

Menetrier, Aubertin. Arch. gen. de Med., 1902, p. 658. 

Monti, Berggrun. Chron. Anaemie d. Kindesalter, Leipzig, 1892. 

Mouisset, Tolot. Rev. de Med., 1902, p. 844. 

Muhlman. Cent. f. Path., 1899, p. 160. 

F. Muller. Verh. d. Vereins. inn. Med., 1888, p. 378. 

R. MuUer. Prag. med. Woch., 1890, No. 17. 

Netter. Progres. Med., 1886, p. 992. 

Netter, Martha. Archiv. de Phvsiol., 1886, p. 7. 

Nicati. Marseilles Med., 1884, p. 684. 

Van Noorden. ^ Path. d. Stoffwechsels, p. 280. ^ ibid., p. 461. 

Oppenheimer. Deut. med. Woch., 1889, Nos. 42-44. 

d'Orlandi. Rev. mens. Mai. I'Enf., 1899. 

Osier, McCrae. N. Y. Med. Jour., vol. Ixxi. p. 757. 

Osterspey. Inaug. Diss. Berlin, 1892. 

Pee. Diss. Berlin, 1890, p. 8. 

Poisseuil. Cited b}^ Grawitz. 

Price- J ones. Middlesex Hosp. Rep., vol. i. p. 113. 

Quincke, Dettwyler. Corresp. Schweiz. Aerzte, 1875, p. 101. 

Reinbach. Langenbeck's Archiv, Bd. 46, p. 486. 

Reinert. Zahlung d. Blutkorp, 1891. 

de Renzi. Virchow's Archiv, Bd. 102, p. 218. 

Rochemont. Miinch. med. Woch., 1897, p. 1466. 

Rogers. Lancet, 1902, II., p. 659. 

Rokowsky. Archiv des Sci. Biol., St. Petersb., 1892, p. 517. 

Rosenstein. Cong. f. inn. Med., 1892, p. 74. 

Sadler. Fort. d. Med., 1892, Suppl. 

Sailer, Taylor. Internat. Med. Mag., 1897, July. 

Schmidt. Charact. d. epidem. Cholera, Leipzig, 1850. 

Schneider. Diss. Berlin, 1888. 

Schneyer. Zeit. f. klin. Med., Bd. 27, p. 475. 

Seligman. Lancet, 1902, I., p. 1764. 

Silherman. ^ Archiv f. Kinderheilk., 1887, p. 401. ^ Deut. med. Woch., 1886, 
p. 497. 

Sittmann. Deut. Arch. klin. Med., Bd. 53, p. 323. 

Stengel, White. Univ. of Penna. Bull., vol. xiv. p. 310. 

Thomson. Cited by Schmidt. 

Vaquez, Rihierre. Compt. Rend. Soc. Biol., 1902, p. 1074. 

Vincent. Semaine Med., 1893, p. 228. 

Weiss. Jahrb. f. Kinderheilk., Bd. 35, p. 146. 

Wlajew. Cited, Baumgarten's Jahresb., 1894, p. 400. St. Petersb. med. Woch., 
1894, Lit. beil., p. 43. 

Zancarol. Revue de Chirurgie, 1893, T. 13. 



CHAPTEE XXI. 

LUNGS, HEART, KIDNEYS. 
DISEASES OF THE LUNGS. 

Respiratory Changes in the Blood. During its passage through 
the kiDgs the blood undergoes certain changes which in their normal 
progress belong to the physiology of the blood, but when disturbed 
by pathological conditions may considerably affect both its chemistry 
and its morphology. 

The absorption of Oo, which results partly by simple absorption 
by the plasma, but largely by chemical union with Hb, raises the 
volume of this gas in arterial blood to 21 per cent., as aganist 12 
per cent, for venous blood, while the discharge of COg from the 
tissues into the plasma, where about two-thirds of it exist as a bicar- 
bonate and one-third in the red cells, increases the CO2 content of 
venous blood to 46 volumes per cent, from 38 per cent., the average 
content of arterial blood. 

The character of the diet considerably influences the ratio of CO2 
excretion to O2 absorption, which with carbohydrate food maintains 
a proportion of about 1 to 1, while with highly albuminous diet more 
oxygen is absorbed and devoted to oxidation, and the ratio is 0.74 to 
1 (Pembry). 

Arterial blood was long supposed to be richer than venous in solids 
and Hb (Kruger), but Cohnstein and Zuntz showed this apparent 
thickening to be due to stasis caused by the procedures followed in 
venesection ; and with Kruger and others these observers demon- 
strated that the blood in larger arteries and veins is equally rich in 
red cells, Hb, and dry residue. 

An important difference between venous and arterial blood was 
demonstrated by Hamburger, who showed that under the influence 
of CO2 the isotonic tension of the red cells is moderately increased, 
so that chlorides and water pass more readily from plasma into cells, 
while albumins, alkalies, and probably also phosphoric acid, pass 
from cells to plasma. A simultaneous increase of the sugar and 
fat of the serum was also noted, but its origin not fully determined. 

As a result of these alterations in osmotic characters, the red 
cells of venous blood were found to swell and assume a more sphe- 
roidal shape. Limbeck, who also verified this change in the 
osmotic qualities of the red cells in venous blood, referred the excess 
of dry residue of the plasma not to withdrawal of albumins from 
the cells, but to absorption of the water of the plasma by the red 
cells, which he found to suffer an increase of volume in venous 
blood. 



408 GEXEF.AL DISEASES OF VISCERA. 

With the increase of COo in venous blood, those observers who 
identify alkalinity with COo-content found an increased acid-neutral- 
izing power in venous blood. This anomalous result, viz., the 
increase of alkalinity of a fluid by the addition of an acid, they 
referred to the withdrawal of alkaline salts from the tissues for the 
neutralization of the acid. 

It is of prime importance, in considering the pathogenesis of symp- 
toms in various anemias, to call attention to several studies which 
have demonstrated that Hb has a strong chemical affinity for oxygen, 
and that this attraction, rather than the percentage of O^ in the air, 
chiefly regulates the supply of oxygen to the tissues. Lukjanow 
first showed that by increasing the pressure of the O2 in the lungs 
he could not add to the quantity of absorbed oxygen, although arte- 
rial blood is not saturated with oxygen, while Lowy found that 
neither by increasing the pressure to 1-400 mg. Hg nor by lowering 
it to 40 mg. (normal 760 mg.) could the blood be made to absorb 
more or less O^. Beyond these points, however, the absorption of 
Go begins to vary. Turning their attention to the respiratory 
processes in anemia, Kraus, Chvostek, Bohland, and especially 
Biernacki, found that the quantity of oxygen that can be exhausted 
from blood remains about the same, although the Hb may vary 
greatly, that in simple anemia the system instead of using less oxygen 
employs rather more than in health, and only in the severest forms of 
anemia is the percentage of oxygen in the blood distinctly reduced. 

It therefore appears, as Grawifz concludes, that the oxygenation of 
the blood in the lungs is not regulated by the laws of diffusion, and is 
not closely dependent upon the atmospheric pressure, nor upjon the 
amount of Hb in the blood, but is governed by a sjjecial chemical 
activity residing in the Hb. 

The laws governing the respiratory changes in the blood, thus 
briefly sketched, principally apply to chemical processes, but have 
important bearing, also, upon certain morphological changes seen in 
conditions of dyspnea, asphyxia, and in the peculiar state of the 
blood observed at high altitudes. 

The exhalation of vapor during respiration, while not followed under 
normal conditions (Dastre) by any concentration of the blood, may, if 
we except the results of Grawitz's observations in pathological states, 
lead to considerable loss of water and increase of red cells and dry 
residue. Grawitz examined the blood of an hysterical woman, 
before and after a prolonged attack of hysterical dyspnea, in which 
the respirations rose to 100 per minute, and found the red cells 
increased from 4,900,000 to 5,110,000, tue dry residue of the whole 
blood from 19.78 per cent, to 22.08 per cent., and that of the serum 
from 9.54 per cent, to 9.85 per cent. A similar result was noted 
after he had voluntarily increased his own respiration to 40 per 
minute, during a period of one hour and three-fourths. 

Asphyxia. During dyspnea from disease of heart or lungs there 
is a proportionate increase of CO2 in the blood (Kraus, Chvostek). 
In extreme asphvxia, Zuutz collected the results of nineteen analyses, 
which gave for O2 0.96 volume per cent, and 49.53 per cent, of COg. 



LUXGS, HEART, KIDNEYS. 409 

In the attempt to discbaro^e COo from the tissues and to supply Og, 
respiration is accelerated, and the same result is attained by the 
polycythemia which results from venous stasis. Among the results 
following the excess of CO^ in the blood is an alteration in the red 
cells w^hich renders the Hb more readily diffusible in the plasma. 
This change, while not apparently leading to hemoglobinemia during 
life, is evident after death in the reddish tinge of the serum. One 
of the prominent signs in the blood of asphyxia is the failure of coagu- 
lation^ which is often very complete and is probably referable to the 
presence of COg. Ottolenghi, examining the blood of asphyxiated 
rabbits, found it to be thinner and more diffusible, while the red 
cells were reduced in number, resistance, and specific gravity. In 
the peripheral blood of the human subject, during rapid asphyxia, 
there are all the evidences of extreme concentration. In the slower 
forms of asphyxia, which are accompanied by pallor, the blood has 
apparently not been compared with that of the more rapid cases. 

Emphysema. The blood in emphysema varies considerably 
according to the state of the circulation and respiration. 

Daring the intervals lohen the circulation is at its best, and cyanosis 
is absent, an anemic condition may be demonstrated in many cases, 
-svhich is referable to the malnutrition of the patients or to compli- 
cations, especially cirrhosis of liver, nephritis, and chronic gastritis. 
When cyanosis becomes chronic, most observers have found more or 
less polycythemia and increase in specific gravity (Peiper,^ Grawitz^), 
but in Leichtenstern's cases this concentration was apparently insuffi- 
cient to obscure the anemia, as he reported a loss of Hb in patients 
suffering from cyanosis, edema, and heart-failure. An increase in 
the volume of red cells up to 8// has been described by Vaquez,^ in 
cases of chrouic cyanosis from various causes. During asthmatic 
aftachs with cyanosis, the blood becomes still further concentrated, 
and the expressed drop may appear almost black. 

The leucocytes are usually of high normal average, but during the 
asthmatic attacks there may be distinct leucocytosis. When bron- 
chitis is added the leucocytes may be markedly increased. With or 
without leucocytosis a considerable proportion of the leucocytes may 
be of the eosinophile variety. Gabritschewsky, who called atten- 
tion to this excess of eosinophiles in the blood corresponding to their 
increase in the sputum of many asthmatic patients, found in three 
cases from 11 to 22 per cent., while Fisk reported 14.6 per cent, in 
one^ease, and Billinurs found as many as 53.6 per cent, out of 8300 
cells. From the observations of Leyden, Van Noorden, and especially 
of Scliwerschewski, it has been shown that excess of eosinophiles 
in the blood of asthmatics occurs principally or only at the time of 
the paroxysm, that they increase with repeated attacks, diminish 
shortly after the paroxysm and with the appearance of expectora- 
tion, and in the intervals largely disappear. Since there is no such 
tendency to eosinophilia in the suffocative attacks of endocarditis, 
nor in the severe dyspnea of Bright' s disease, the examination of the 
blood rnay serve to distinguish bronchial asthma from other forms of 
dyspnea, and may perhaps indicate the approach of a paroxysm. 



410 GENERAL DISEASES OF VISCERA. 

Teichmiiller and Fuchs, however, find many eosinophile cells in 
other forms of bronchitis. 

Bronchitis. Acute catarrhal bronchitis of ordinary severity and 
affecting the larger bronchi only, has little effect upon the red cells, 
and seldom raises the number of leucocytes. In some severe cases 
the writer has found as many as 15,000 white cells, when the patient's 
temperature was 104°. In some of Cabot's cases the leucocytosis 
was slightly higher. In seven children between three and seven 
years of age, Stengel and White observed moderate polynuclear 
leucocytosis, 13,000 to 19,000 cells. 

Capillary bronchitis, with high temperature and marked prostra- 
tion, may strongly resemble lobar pneumonia in clinical features, and, 
like pneumonia, is accompanied by marked leucocytosis. In three 
fatal cases with high temperature, dyspnea, and cyanosis, the writer 
found 18,000 to 37,000 leucocytes. At autopsy there were signs 
of severe general bronchitis, no consolidation, but well-marked 
chronic nephritis. In two cases without autopsy, Cabot found as 
high as 41,000 leucocytes. 

DISEASES OF THE HEART. 

The majority of observations on the blood of chronic endocarditis 
have shown more or less continuous polycythemia and concentra- 
tion of the blood. The more important of these studies have been 
contributed by Nasse, Naunyn, Toenissen, Bamberger, Lichtheim, 
and Reinert,^ who have referred this concentration to stasis from 
local vasomotor or general cardiac paresis, to transudation of serum, 
or (Naunyn) to a physiological effort on nature's part to furnish more 
oxygen by increasing the cells and Hb of the blood. 

The opposite condition of hydremia has been found more usual 
or regarded as more important by Leichtenstern, Oertel, Oppen- 
heimer, Stintzing and Gumprecht, and many others, who hold that 
an excess of lymph from various sources passes into the vessels, as 
a result of lowered blood pressure. Schneider and Limbeck find 
that while mitral lesions are usually associated lolth polyeythemia, aoi^tie 
insufficiency more often leads to hydremia. 

All observers are agreed that the valvular lesion, and the usual 
causes leading to it, exert little or no effect upon the blood, and, 
while differing as to their significance, all admit that the changes in 
the blood vary considerably at different periods of the disease. 

The conflicting views have been carefully studied and partially 
unified by Grawitz, who finds that the blood shows three different 
states, according to the stage of the disease, and determined chiefly 
by the degree of compensation established in the heart: 

1. When valvular lesions are fully compensated by cardiac hyper- 
trophy, and when there are few or no symptoms of disease of this 
or other organs, the state of the blood depends entirely on the con- 
stitution and state of nutrition of the individual. 

2. When disturbances of compensation begin, when the heart 
muscle fails and the pulse is accelerated, and dyspnea and its train of 



LLW^GS, HEART, KIDNEYS. 411 

symptoms appear, changes occur in the blood which are clearly 
referable to the diminished force of the heart. 

The whole blood loses in specific gravity and in dry residue, 
while its content of water increases, and these changes are more 
marked in the veins than in the superficial capillaries. The red 
cells are reduced in number, but they suffer no changes in size or 
in Hb-content. The leucocytes show no characteristic changes. 
The blood serum shows the most marked changes, always becoming 
more watery. These alterations Grawitz refers solely to the lowered 
blood pressure, which is followed bv dilatation of capillaries and 
passage of tissue fluids into the blood stream. Oliguria may result 
from the same factors, but is not the cause of the hydremia. 

3. When chronic venous stasis is established, and dyspnea, cyano- 
sis, and edema exist, the changes in the blood are more complicated. 

Under these circumstances the blood loses water, becomes richer 
in red cells, and more so in the capillaries than in the veins. These 
effects Grawitz believes to result from transudation of fluids through 
the capillaries into the tissues, but increased exhalation from the 
congested lungs, and possibly also increased evaporation from the 
skin, contribute to the same result. When the balance of pressure 
between capillaries and tissues has been adjusted, any added failure 
of the heart may be followed by still lower pressure and temporary 
hydremia. 

Grawitz's deductions have appeared to most critics to be only partially valid. 
In the first stage it is generally agreed that the blood is usually normal, and it 
is also fully demonstrated that a fall of blood pressure leads to relative hydre- 
mia, but his explanation of the origin of the polycythemia of chronic endo- 
carditis has not proven fully satisfactory. As Limbeck points out, many 
patients always show some reduction of red cells whether compensation is 
complete or not; while others show considerable variations in red cells with- 
out apparent relation to the action of the heart, the presence or absence of 
edema, or the activity of the kidneys. Limbeck, therefore, attributes less im- 
portance to the interchange of fluids between the blood and tissues, and 
believes that the polycythemia of heart disease is partly referable to the same 
obscure factors which increase the red cells in high altitudes. That there is an 
actual new formation of red cells in the polycythemia of endocarditis is held 
by Marie, Reinert,^ and others. 

Without entering further into the details of individual opinions, it 
appears certain from the studies already cited, and from others con- 
tributed by Siegl, Peiper,^ Schmaltz, Bauholzer, Maxon, Stintzing 
and Gumprecht, that : 

1. In advanced endocarditis with failing compensation there is a 
distinct tendency toward concentration of the blood, which at times 
increases the red cells to 8,000,000 or more. 

2. This polycythemia is the combined result of venous stasis, 
dyspnea and cyanosis, transudation of blood serum, and possibly 
also of other obscure factors which lead to polycythemia in high 
altitudes. 

3. The state of the blood in chronic endocarditis responds to a 
limited extent, but not invariably, to diuretics, diaphoretics, purges, 
and heart tonics. 



412 GENERAL DISEASES OF VISCERA. 

4. The coiistaot tendency toward anemia is usually masked by the 
peculiar condition of the circulation. 

5. The result of the examination of the blood must be interpreted 
with strict regard to the general condition of the patient. 

Results of Blood Examinations in Chronic Endocarditis. The fore- 
going statements are fully borne out by a review of the reported 
examinations of the blood in endocarditis. In some series of cases 
the polycythemia is very uniform, as found especially by Oppenheimer 
and Reinert, while the Hb commonly runs from 90 to 110 per cent. 
Usually the red cells do not exceed 6,000,000, but some cases with 
cyanosis reach 7,000,000 or even 8,000,000. On the other hand, a 
slight reduction of cells, not below 4,000,000, appears in most cases 
reported by other observers. Maxon's statement that the blood of 
heart disease commonly shows slight variations above or below the 
normal in red cells, specific gravity, and albumins, is the only rule 
of general application. 

That aortic insufficiency is usually found with less concentrated 
blood is also apparent in nearly all comparative studies (Schneider, 
Grawitz, Limbeck, Menicanti, Reinert, Hayem, Sadler). Yet even 
here the red cells seldom fa'l below 4,000,000. 

Variations from the abov^e rules are not unknown, as some cases 
with cyanosis have shown less than 4,000,000 red cells, and the 
aortic insufficiency may lead to polycythemia. Much depends upon 
the particular circumstances surrounding each patient, which must 
always be regarded with care 

The LEUCOCYTES in uncomplicated cases show no important varia- 
tions from the normal, but with concentrated blood they are apt to 
be rather above the average normal figures. During the febrile 
periods which mark the terminal stages of many cases, leucocytosis 
of considerable grade is usual. The complications of endocarditis 
w^hich cause leucocytosis are numerous, and antemortem leucocytosis 
is usually prolonged and pronounced. 

Malignant Endocarditis. The more acute cases of bacterial 
endocarditis furnish some of the most typical examples of septicemia, 
in which the blood shows rapid loss of cells, albumins, and Hb, 
leucocytosis, and very often bacteria in demonstrable numbers. 

The anemia of malignant endocarditis is of rapid progress and 
usually becomes one of the characteristic features of the disease. 
Beginning in patients with practically normal blood, the septic process 
often reduces the red cells within two to three weeks to 3,500,000 
or 3,000,000, or even lower. In some cases, usually those of longer 
duration, the anemia is less marked (over 4,000,000 cells), or is 
masked by the febrile process and by venous stasis. In all the 
markedly septic cases, however, the anemia becomes severe. In the 
later stages of severe cases the evidences of destruction of red cells 
become marked, the Hb is very deficient and may become dissolved 
in the plasma, shadow corpuscles appear in the fresh specimen, and 
various forms of degeneration of red cells are demonstrable in the 
dry specimen. In such cases the red cells may not number much 
over 1,000,000. After death the deposits of blood pigment in the 



LUNGS, HEART, KIDNEYS. 413 

viscera are very abundant and closely simulate those of pernicious 
malaria, for which they may readily be mistaken. 

Leucocytosis is present probably in all cases, but is often intermittent 
and single observations may fail to discover it. In this, as in other 
forms of sepsis, there may be a tendency to slight leucocytosis with 
high proportion of polynuelear cells, and in general the increase of 
w^hite cells is not very marked, considering the condition of the 
patient. Eoscher and Cabot report fatal cases with 8000 and 8900 
leucocytes shortly before death, while Krebs found antemortem 
leucocytosis of 44,200, and Grawitz reported 168,000. 

Bacteriological examination of the blood is often required in the 
diagnosis of obscure cases. From the rather limited number of 
recorded examinations by reliable methods it appears that bacteria 
are always to be found in the blood in a certain group of cases of 
ulcerative endocarditis. These cases include the examples of crypto- 
genic infection which run an acute septic course and end fatally 
within a few weeks or months. In the cases of ulcerative endo- 
carditis which terminate with septic fever, and in which an acute 
process is often added to the chronic lesion, cultures of the blood are 
usually negative. Grawitz' s claim that repeated negative cultures 
are sufficient to rule out ulcerative endocarditis, cannot, however, be 
admitted ; for the evidence rather favors Kuhnau's view that the 
difference between ^^ simple" ulcerative and malignant endocarditis 
is one of degree, not of kind, and that in many cases of subacute or 
chronic ulcerative endocarditis or bacterial origin the blood is sterile. 

These groups of cases are illustrated by the reports of several investigators. 
Grawitz^ examined 7 cases of suspected ulcerative endocarditis, all of which 
gave negative cultures, but only 1 of which proved to have an ulcerative 
lesion. In 3 pronounced cases of malignant endocarditis he obtained in 
2 staphi/lococcus pyogenes aureus, in 1 diplococcus lanceolatus. Kraus ex- 
amined the blood in 7 cases, finding the streptococcus in ], negative cul- 
tures in 6- Petruschky, examining the blood from a wet cup, obtained the 
strepfococcvs pyogenes in 1, and a negative result in the other, of 2 cases. 
Kuhnau had only 1 positive result {staphylococcus pyogenes aureus) in 12 
cases examined. Colin in 2 acute cases found in 1 both streptococcus pyo- 
genes and staphylococcus aureus, and in the other staphylococcus aureus alone, 
while in 2 chronic cases the cultures were negative. James and Tuttle 
obtained positive cultures in 3 of 4 fatal cases, once tinding the diplococcus 
lanceolatus. White obtained negative results in 2 cases three to four days 
before death, but isolated staphylococcus pyogenes aureus from both just before 
death. The writer, using 5 to 10 c.c. of blood drawn from the median basilic 
vein, obtained pure cultures of streptococcus pyogenes m 2 typical cases of 
maHgnant endocarditis. These patients gave no history of cardiac disease 
until the development of a septic febrile process, which continued without 
intermission for one to six months, and until death. In 4 cases of chronic 
ulcerative endocarditis ending with septic fever cultures of the blood were 
negative. 

Gonorrheal Endocarditis. The gonococcus has been obtained 
in pure culture from the circulating blood of cases of endocarditis 
by Thayer and Blumer, and Thayer and Lazear, and Halle. In all 
cases the blood was extremely anemic, red cells under 2,000,000, 
while the leucocytosis was slight, 12,000 to 14,000 in one case, and 
8500 to 18,000 in the others. Many cases of gonorrheal septicemia 



414 GENERAL DISEASES OF VISCERA. 

collected by these authors indicate the frequency with which this 
germ is probably connected with endocardial lesions. 

Colunibini also obtained the gonococcus in cultures of the circu- 
lating blood in a case of gonorrheal septicemia with endocarditis, 
and demonstrated its identity and pathogenic qualities in the human 
urethra. 

McCallum and Hastings report a case of acute endocarditis from 
which they obtained from the circulating blood cultures of a some- 
what peculiar coccus resembling streptococcus pyogenes. 

Significance of the Bacteriological Examination of the Blood in Endo- 
carditis. 1 . A. positive result when obtained under proper precau- 
tions, and long enough before death to avoid antemortem secondary 
infections, places beyond doubt the infectious nature of the process. 

2. A negative result does not indicate that the vegetations do not 
contain bacteria in their substance or on their surface. A large 
number of negative bacteriological examinations of the blood have 
been recorded in cases showing, postmortem^ various bacteria in and 
on the inflamed heart valves. 

From personal experience of moderate extent the writer has drawn the 
impression that when malignant endocarditis follows the type of pure septi- 
cemia with cardiac symptoms in the background, bacteriological examination 
of the blood is usually positive, but when cardiac symptoms are or have been 
prominent, bacteriological examination of the blood is usually negative. 

Congenital Heart Disease. The pronounced cyanosis from which 
most of these patients suffer leads to extreme degrees of concentra- 
tion of the blood, as the following cases will show : 

Specific 
Author, Red cells. Leucocytes. Hb^c. gravity. 

Krehl 8,000,000 

Vaquez2 8,900,000 

Banholzer 9,440,000 160 1.071 

8,470,000 12,000 110 

Gibson 6,700,000 12,000 92 

Carmichael . 8,100,000 16,000 

8,820,000 

Toenissen 7,540,000 

Cabot 8,430,000 

Townsend has recently reported thirteen cases in which the red 
cells varied between 5,600,000 and 11,800,000. 



DISEASES OF THE KIDNEY. 

The existence of marked hydremia in cases of nephritis was 
demonstrated in several earlier studies of the chemistry of the blood 
(cited by Gorup-Besanez), but Schmidt's analyses first clearly showed 
the more exact nature of this hydremia. 

In three patients with albuminous urine and marked edema, he found con- 
siderable loss in specific gravity of the whole blood (1.043 to 1.051), and of the 
serum (1.018 to 1.024), while the red cells remained nearly normal in gravity 
(1.081 to 1.084), but were much reduced in bulk (34.2 from 44.9 per cent.). These 
changes were believed to result largely from the loss of albumins of the serum, 
while the Hb of the red cells and the salts of the plasma were but slightly 



LUNGS, HEART, KIDNEYS. 415 

affected. Scherer's analyses in six cases demonstrated a decrease in the solids 
of the whole blood, and a loss of 5 per cent, of the albumins, although the 
fibrin was sometimes increased. The red cells were reduced, but their dry- 
residue relatively increased. Although the serum was very watery, the dry res- 
idue averaging 6.9 per cent,, the salts of the serum were increased. Very low 
gravity of the serum, 1.019 to 1.023, was also noted by Becquerel and Rodier. 

From numerous other analyses by Frerichs, Gorup-Besanez, Hinterberger, 
and others, it began to appear that the composition of the blood varies considera- 
bly in different stages of the disease, and later studies have shown that the two 
main clinical and pathological types of the disease, the chronic exudative and 
the chronic productive without exudation, are attended with distinct changes 
in the blood. 

Chronic Exudative (Parenchymatous) Nephritis. The albu- 
minuria and edema of this group of cases are associated with well- 
marked anemia, which, however, is subject to great variations on 
account of the intermittent course of the disease and of the frequent 
disturbing effects of treatment. 

The usual condition of the blood is one of moderate chlorotic 
anemia. The majority of cases show between 3,000,000 and 5,000,000 
red cells and 40 to 80 per cent, of Hb. The reported series of 
cases in the literature show wide variations in the condition of the 
blood. Considerable polycythemia is not infrequently encountered. 
Leichtenstern and Sorensen found little reduction of Hb and an 
average of 4,740,000 red cells, while Laache and Reinert^ found a 
low Hb percentage with slight loss of cells. These changes represent 
the condition most commonly found. Cases with less than 2,000,000 
cells are reported by Grawitz, Sadler, Cabot, and are not rare. In 
these and occasionally in other cases the writer has sometimes found 
a high or increased Hb-index, and at autopsies in cases of pernicious 
anemia has several times found the lesions of chronic productive 
nephritis with exudation. 

These variations are well illustrated by Cabot's synopsis of thirty- 
five cases from the Massachusetts General Hospital : 

Red cells. Cases. Red cells. Cases. 

6,000,000 to 7,000,000 ... 3 3,000,000 to 4,000,000 ... 11 

5,000,000 to 6,000,000 ... 6 2,000,000 to 3,000,000 ... 2 

4,000,000 to 5,000,000 . . .12 1,000,000 to 2,000,000 ... 1 

The attempt to analyze the causes of the variations of the anemia 
in chronic nephritis is met with difficulties, and numerous factors 
must be considered. Polycythemia results from cyanosis, disturbance 
of circulation, and rapid transudations, and each of these conditions 
may and frequently does obscure pronounced anemia. An astonish- 
ing degree of pallor of the face may thus be found with 5,000,000 
red cells and 100 per cent, of Hb. The progressive anemia of the 
average case is clearly referable to the loss of albumins of the serum 
and general malnutrition. Yet the real advance of the anemia is 
often disturbed by the intermittent losses of albumin and attacks of 
edema. While Benczur and Czatary, and v. Jaksch^ believe that 
the hydremia is not proportionate to the edema, yet Bogdanow, and 
Stintzing and Guraprecht have shown a positive connection between 
hydremia and edema, and have noted an improv^ement in the blood 
following improvement in general symptoms. 



416 GENERAL DISEASES OF VISCERA. 

The relatively high Hb-index is apparently the natural result of 
a loss of albumin which affects principally the serum. The gravity 
of the red cells has been found uniformly high by most analysts since 
the time of Scherer. 

Grave or pernicious anemia develops in a small proportion of cases 
of chronic parenchymatous nephritis, and appears at times to result 
directly from nephritis. It must be referred to the repeated losses 
of albumin from the blood and to the general disturbance of nutri- 
tion, but it is probable that the very severe grades of anemia result 
from the combined effects of lesions in several viscera, including 
chronic gastritis, cirrhosis of liver, arteriosclerosis, etc. 

Chemistry. Chemical analysis gives the clearest insight into the 
changes in the blood in nephritis. The specific gravity is regularly 
reduced. Peiper^ found a gravity of 1.026 in a very anemic child, 
but after marked improvement four weeks later the gravity was 
1.055. Similar variations, usually between these limits, are reported 
by various observers. The changes in the serum demonstrated by 
the older observers have been verified by many later studies. The 
gravity of the serum is much reduced (as low as 1.013, Bostock), 
and its volume remains high. While considerable relation has been 
found to exist between the changes in the blood and the albuminuria 
and edema (Stintzing, Gumprecht, Bogdanow), the immediate effects 
of transudates and albuminuria are not always evident (v. Jaksch). 
Hammarschlag, who found the gravity of the serum between 1.018 
and 1.030, concluded that edema has more effect upon the gravity of 
the serum than has albuminuria ; and that ivhen edema is absent the 
gravity of the serum is usually aboid normal. 

The leucocytes in chronic nephritis are usually normal or subnormal 
in number. Cabot found no leucocytosis in thirty-one of forty 
unclassified cases, while in fourteen of nineteen uremic cases there 
was leucocytosis, reaching 44,000 in one eclamptic patient. Other 
reports show similar variations, and it is evident that the behavior 
of the leucocytes in chronic nephritis depends upon accidental con- 
ditions and complications. 

Chronic Interstitial Nephritis. (Contracted Kidney.) The 
absence of edema and marked albuminuria in cases of chronic neph- 
ritis without exudation allows the blood to remain practically normal, 
at least during the latent progress of the disease. Many patients 
are carried off by acute uremia and other terminations of interstitial 
nephritis before the blood is markedly altered. If at any time in 
the pr()o;ress of the disease there are exacerbations marked by exuda- 
tion, all)uminuria, and edema the blood suffers for a time as in 
chronic nephritis of more distinctly exudative type. After the 
exudative period the blood is partially restored, but a certain grade 
of chlorotic anemia is apt to persist. 

That chronic nephritis may run its course without giving notable changes 
in the blood, or, indeed, any other pronounced symptoms, is a well-attested 
fact, of which the writer has seen at autopsy at least one instance. This 
subject was an able-bodied policeman, dying of acute colitis, whose kidneys 
were shrunken to an extreme degree. The blood and urine were normal 
shortly before death. 



LUXGS, HEART, KIDNEYS. 417 

On the other hand, very severe grades of anemia, usually of micro- 
cytic type, are sometimes associated with chronic diffuse nephritis 
without exudation. Some of these cases are partly referable to lead 
poisoning, which has initiated the renal lesion and damaged the 
blood. In others there is advanced arteriosclerosis with frequent 
hemorrhages from the nose, kidneys, or other regions. In still 
others no reasonable explanation of the anemia is to be found. 

Grawitz recognizes two stages in this disease : one in which the heart and 
circulation and the blood are normal ; and a second in which compensation 
fails in the hypertrophied heart, and the blood suffers the same changes as in 
uncompensated valvular disease. The importance of the condition of the 
heart in determining the blood changes in nephritis is very great and has 
already been considered in the references to edema and cyanosis but failure of 
the left ventricle with feeble pulse is more common with the large white than 
with the small contracted kidneys. The writer is, therefore, unable to recog- 
nize the above stages in the course of the contracted kidney, finding them 
more evident in the cases of chronic diffuse nephritis with exudation, and in 
patients with albuminuria and edema. 

Acute Nephritis. The changes in the blood in acute nephritis 
with albuminuria and edema resemble those of the same type of 
chronic nephritis. Peiper found no diminution in specific gravity 
in an acute case. Laache and Bogdanow observed more rapid, 
sev^ere, and more variable changes in the acute than in the chronic 
cases, while v. Jaksch concluded that in both forms the changes 
were about equally variable. Hayem found no considerable loss of 
red cells except in hemorrhagic cases. Many other isolated reports 
show all but the very severe grades of anemia developing within a 
few weeks, sometimes very rapidly. 

Leucocytosis (maximum, 22,000) has been observed in a consid- 
erable proportion of cases by Hayem, Sadler, and Cabot, the latter 
author referring the persistent increase to loss of blood by the kidney. 

None of these observers has attempted to connect the behavior of the 
leucocytes with the character of the lesion in the kidneys. It would seem 
that the productive inflammation could run a fatal course without leucocytosis, 
that simple acute exudative nephritis might be accompanied by a moderate in- 
crease of white cells, and that acute idiopathic or secondary purulent nephritis 
must nearly always be accompanied by marked leucocytosis. Unfortunately 
there are no reports at hand on which to base these conclusions. Profuse 
hemorrhage, uremic attacks, and complicating infections may be responsible 
for occasional leucocytosis, but Sadler's negative cases show that much albu- 
min, many granular casts, and blood cells may be present in the urine when 
the leucocytes in the blood are not increased. 

Uremia. Chemistry. Very numerous chemical analyses of the 
blood in uremia have failed as yet to demonstrate the true nature of 
this intoxication. Urea in the blood was believed by Frerichs to 
be the particular toxic agent in uremia, and although this principle 
has been demonstrated in abnormal quantities in the blood of uremic 
coma by Spiegelberg, Hoppe-Seyler, Bartels, and others, it was 
shown by Landois that intravenous injections or local applications to 
the medulla of large quantities of urea exert no toxic influence. 
Neither has its derivative, ammonium carbonate, been found in the 
blood, nor shown to exert a toxic influence on the nervous system 

27 



418 GENERAL DISEASES OF VISCERA. 

(Kulme, Strauch). Kreatixin, believed by Schottin and Perls to 
be the active agent, has likewise been set aside, although this sub- 
stance is increased in the blood of uremic subjects. Potassium has 
been found in considerable excess in the blood by Feltz and Ritter, 
and by Astaschewsky, who regard uremia as a form of potassium 
poisoning. Although Sneyers and Horbaczewsky failed to find an 
excess of potash salts in eclamptic and uremic subjects, this theory 
has received more recent support from Bouchard, Roger, Povighi, 
and others, who offer evidence to show that potassium is one of 
several poisonous substances which accumulate in the blood in uremia. 
Limbeck has shown, however, that while an excess of potash can be 
obtained from the blood of uremic dogs, he could get no such excess 
if the blood was examined before death. 

Diminished alkalescence was first noted in uremic blood by 
V. Jaksch,^ and subsequently by Peiper,^ Rumpf, Mya and Tas- 
sinari, Limbeck, and others, who have shown that the alkalescence 
diminishes greatly on the approach of uremic symptoms. Branden- 
burg found the alkali-tension greatly diminished in uremia. The 
attempt to establish this theory of acid intoxication has, however, 
not been successful. Although uric acid may be in excess in uremia, 
it is also quite as much increased in many other conditions. Fatty 
acids and phosphoric acids were not found in excess by Limbeck, 
who, indeed, was unable to demonstrate a deficiency of CO2 in all 
cases of experimental uremia. Diminished alkalescence appears 
more probably to be only a secondary condition of the blood in 
uremia. 

The present tendency is to regard the uremic seizure as the result 
of toxic action of a variety of nitrogenous metabolic products which 
are supposed to be retained in the system or at times thrown off in 
excess in the urine. Bouchard and others have isolated from the 
urine a variety of toxic principles, inckiding ptomains and urotoxins, 
some of which produce convulsions; others are narcotic, while still 
others lower temperature, contract the pupil, or produce salivation. 
Although the actual existence of these principles has been denied 
(Stadthagen), and the urine has not always been found so toxic as 
Bouchard claims it to be (Fleischer), the autotoxic theory is gener- 
ally regarded as approaching most nearly to the true explanation of 
uremia. One of the chief objections to it consists in the fact that 
uremic attacks frequently arise at periods when the excretion of 
urine is much improved. 

BiBLIOGKAPHY. 

Diseases of Heart, Lungs, Kidneys. 

Astaschewsky. St. Petersb. med. Woch., 1881, No. 27. 
Bamberger. Wien. klin. Woch., 1888, No. 1. 
Banholzer. Cent. f. inn. Med., 1894, p. 521. 
Bartels. Ziemssen's Handb., Bd. 9, p. 1. 
Benczur, Czatary. Deut. Archiv klin. Med., Bd. 46, p. 478. 
Biernacki. Cent. f. inn. Med., 1895, p. 337. 
Billings. N. Y. Med. Jour., vol. Ixv. p. 691. 
Bogdanow. St. Petersb. med. Woch., 1875. 



LUNGS, HEART, KIDNEYS. 419 

Bohland. Berl. klin. Woch., 1893, p. 417. 

Bostock. Cited by Bart els. 

Bouchard. Lecoiis s. 1. Autointox., Paris, 1887. 

Carmichael. Edin. Hosp. Reports, 1894, p. 298. 

Chvostek. Wien. klin. Wocli., 1891, Nos. 6, 7. 

Cohn. Deut. med. Woch., 1897, p. 136. 

Cohnstein, Zuntz. Pfliiger's Archiv, Bd. 42. 

ColumUni. Cent. f. Bact., 1898, Bd. 24, p. 955 

Copeman. Brit. Med. Jour., 1891, I., p. 161. 

Dastre. Semaine Med., 1893, p. 580. 

Feltz, Ritter. De I'Uremie exper., Paris, 1881. 

Fink. Diss. Bonn, 1890. 

Fleischer. Verh. Cong. inn. Med., 1885, p. 307. 

Frerichs. Nervenkrankheit. Braunschweig, 1851. 

Fuchs. Deut. Archiv klin. Med., Bd. 63, p. 427 

Gabritschewsky. Archiv f. exper. Path., Bd. 28, p. 83. 

Gibson. Lancet, 1S95, I., p. 24. 

Gorup, Besanez. Archiv f. phys. Heilk., 1849, p. 514. 

Grawitz ^ Charite-Annalen, Bd. 19, p. 154. 

Halle. Annal. d. GvnecoL, Bd. 50, p. 179. 

Hamburger. Du Bois-Ravmond's Archiv, 1892, p. 513. Suppl. Bd., 1893, 
p. 157. 

Hammarschlag. Zeit. klin. Med., Bd. 21, p. 475. 

Hinterberger. Archiv f. physiol. Heilk., 1849. 

Hoppe-Seijler. Phvsiol. Chem., 1881. 

Horbaczewskij. Med. Jahrb. Wien., 1883, p. 385. 

V. Jaksch. ' Zeit. f . klin. Med., Bd. 23, p. 187. ^ Zeit. f. klin. Med., Bd. 13, 
p. 350. 

James, Tuttle. Presbyterian Hosp. Reports, N. Y., vol. iii. p. 44. 

Kraus. Zeit. f. Heilk., Bd. 17, p. 117. Zeit. f. klin. Med., Bd. 18, p. 160; 
Bd. 22, p. 449. 

Krebs. Inaug. Diss. Berlin, 1893. 

Krehl. Deut. Archiv klin. Med., 1889. 

Kruger. Zeit. f. Biol., 1890, Bd. 8, p. 452. 

Kuhnau. Zeit. f. Hygiene, Bd. 25, p. 492. 

Kuhne, Strauch. Cent. f. inn. Med., 1864, No. 36. 

Laache. Die Anaemie, 1883. 

Landois. Die Anaemie, Wien, 1891. 

Leichtenstern. Untersuch. u. d. Hb-gehalt, etc., Leipzig, 1878, p. 88. 

Leyden. Deut. med. Woch., 1891, p. 1085. 

Lichtheim. VII. Cong. inn. Med., 1888. 

Lowy. Pfliiger's Archiv, Bd. 58, p. 409. 

Lukjanow. Grundriss ein. allg. Path. d. Gefasssystems, Leipzig, 1894. 

McCallum, Hastings. Jour, of Exper. Med., 1899, p. 521. 

Marie. Semaine Med., 1895, No. 4. 

Maxon. Deut. Archiv klin. Med., Bd. 53, p. 399. 

Menicanti. Deut. Archiv klin. Med., Bd. 50, p. 407. 

Mya, Tassinari. Archiv p. 1. sci. med., 1886, No. 20. 

Naunyn. Corresp. Schweizer Aerzte, 1872, p. 300. 

Van Noorden. Zeit. klin. Med., Bd. 20. p. 98. 

Oertel. Deut. Archiv khn. Med., Bd. 50, p. 293. 

Oppenheimer. Deut. med. Woch., 1889, Nos. 42-44. 

Ottolenghi. (Ref.) Allg. med. Central-Zeitune, 1894, p. 724. 

Peiper. ^ Cent. f. klin. Med., 1891, p. 217. ^ Virchow's Archiv, Bd. 116, p. 337 

Pembry. Text-book of Phvsiol. (Schafer), I., p. 717. 

Perls. Berl. klin. Woch., 1868, No. 19. 

Petruschky. Zeit. f. Hj^giene, Bd. 17, p. 59. 

Reinert. ^ Zahlung d. Blutkorp, 1891, p. 199. ^ Miinch. med. Woch., 1895, 
pp. 305, 345. 

Rogers. Action du foie sur 1. poisons, Paris, 1887. 

Roscher. Inaug. Diss. Berlin, 1894. 

Rovighi. Ri^dsta clin., 1886. 

Ru77ipf. Cent. f. klin. Med., 1891, p. 441. 

Sadler. Fort. d. Med., 1891, Suppl. Bd. 

Scherer. Haeser's Archiv, Bd. 10, p. 121. 



420 GENERAL DISEASES OF VISCERA. 

Schmaltz. Deut. med. Woch., 1891, No. 16. 
Schmidt. Zur Charac. d. epidem. Cholera. 
Schneider. Diss. Berlin, 1888. 
Schottin. Archiv f. physiol. Heilk., 1853, p. 170. 
Schwerschewski. Cent. f. inn. Med., 1895, p. 183. 
Siegl. Wien. klin. Woch., 1891, p. 606. 
Sneyers. Path. d. Nephritis chron., Brussels, 1886, p. 144. 
Sorensen. Cited b}' Grawitz. 
Spiegelberg. Archiv f. Gvnecol., 1870, p. 383. 
Stadthagen. Zeit. f. klin."' Med., Bd. 15, p. 383. 
Stengel, White. Univ. of Penna. Bull., vol. xiv. p. 310. 
Stintzing, Gumprecht. Deut. Archiv klin. Med., Bd. 53, p. 465. 
Teichmuller. Deut. Archiv klin. Med., Bd. 60, p. 576; Bd. 63, p. 444. 
Thayer, Lazear. Jour. Exper. Med., 1899, p. 81. 
Toenissen. Diss. Erlangen, 1881. 

Townsend. Boston Med. and Surg. Jour., vol. cxlii. p. 426. 
Vaquez. ' Compt. Rend. Soc. Biol., 1895, p. 142. ' Traite de Med. (Charcot), 
v., p. 298. 

White. Jour, of Exper. Med., 1899, p. 425. 
Zuntz. Hermann's Handb., IV., 2, p. 43. 



CHAPTEK XXII. 

MALIGNANT TUMOES. 
CARCINOMA. 

The impression obtained by individual observers of the effect of 
carcinoma upon the blood has largely depended upon the class of 
cases encountered. 

In active hospital wards the cases are usually advanced, cachexia 
is distinct, and routine examination of the blood shows, as a rule, 
marked reduction of red cells, low Hb-index, and moderate but dis- 
tinct leucocytosis. In dispensaries the earlier stages of the disease 
are encountered, cachexia and palpable tumors are not always noted, 
many tentative diagnoses stand with positive cases, and the blood 
very often fails to show any pronounced alteration. 

In a considerable group of cases the progress of the usual anemia 
is interrupted, however, for unknown reasons, and while the patient 
emaciates, the blood appears to maintain its standard. Hampeln, 
Neubert, Dehio, and others, therefore, speak of an anemic and a 
marantic type of carcinoma. Neubert's cases, five esophageal and 
four gastric, were especially adapted to illustrate the differences, but 
both types may occasionally be seen in other forms of the disease — 
e. g., cancer of uterus. 

Many careful studies have shown that in the earlier recognizable 
stages of the disease, and in somewhat more advanced phases of visible 
growths, the blood remains practically normal. Few published series, 
however, show so large a proportion of cases with red cells above 
4,000,000 as does Cabot's, in which thirty-four of one hundred and 
fourteen cases of carcinoma of stomach gave over 4,000,000 and 
twenty-five over 5,000,000 red cells. Yet this series may well serve 
to emphasize the fact that carcinoma commonly exists in otherwise 
healthy subjects, and for a time fails to reduce the number of red 
cells. The significance of a normal red-cell count is, of course, 
limited by the fact that in many situations the growth tends to retard 
the ingestion and absorption of fluids and thus to concentrate the 
blood. Yet in some instances the malignant growth, like tubercu- 
losis, appears to exert some obscure concentrating influence on the 
blood, and even at death, although the body is emaciated, the blood 
may be unusually deep red. 

Osterspey found 5,000,000 red cells and 98 per cent, of Hb three months 
after the symptoms of a gastric cancer were developed, while in a patient who 
had lost one hundred pounds in weight within a year from gastric cancer he 
found 4,544,000 red cells and 82 per cent, of Hb. Price-Jones reports a case 
of long-standing cancer of the breast with extensive general metastases in 



422 GENERAL DISEASES OF VISCERA. 

which the blood at death showed 6,960,000 red cells and 95 per cent. Hb. For 
one month before death there was a progressive increase in the number of red 
cells. The patient took very little nourishment. Of 114 cases of gastric 
cancer Cabot reports over 5,000,000 red cells in 25, and over 6,000,000 in 4. 
Laache, who noted the same apparent immunity of the blood against the 
effects of a bleeding uterine carcinoma, concluded that there is an individual 
insusceptibility to the effects of malignant tumors. 

It is, nevertheless, time that in the majority of carcinomata, the first 
appear anee of cachexia is accompanied by a corresponding oligocy- 
themia. Cancers of the stomach are among the more active in reduc- 
ing red cells, and some of them, even while remainiug of small size, 
lead to the changes of pernicious anemia. Grawitz counted only 
500,000 red cells in one extreme case of gastric cancer. Of com- 
plications, hemorrhage and ulceration usually affect the red cells 
promptly. Rapid growth and numerous metastases also have a 
similar tendency, but probably less marked. 

Morphologically, the red cells in carcinoma, while presenting the 
usual degenerative changes of secondary anemia, do not show any 
special peculiarities. The usual changes are those of well-marked 
chlorotic anemia with considerable deficiency of Hb, but with 
moderate changes in size and shape. Grawitz found granular degen- 
eration of many cells in ten cases of cancer of the stomach or esopha- 
gus, but none in two cases of uterine cancer. The writer finds that 
in those cases in which the appearance of the blood suggests perni- 
cious anemia the deficiency of Hb, even in the majority of megalo- 
cytes, is nearly always quite distinct. 

Mouisset has also called attention to this fact, finding the Hb-index in 
these cases to be quite as low as in chlorosis. In a case of Daland's, the 
hematocrit gave rather fewer red cells than the hematocytometer, but in per- 
nicious anemia the volume of the red cells is usually much above normal 
(cf. Moraczewsky). 

Nucleated red cells are commonly seen when the anemia is severe, 
and in some cases of gastric cancer they may be extremely abundant. 
Usually these cells are of normal size, but megaloblasts appear in 
the severest cases. It has been suggested that the predilection for 
the bone-marrow as the seat of metastases is responsible for the large 
number of nucleated red cells seen with many advanced carcinomata 
(Epstein). They are frequently seen, however, in the early stages 
of the growth and when anemia is slight. Cabot found them in 
four-fifths of all the severe cases, Schreiber when the Hb was 
normal, and Price- Jones when the red cells numbered 6,390,000. 

The hemoglobin usually begins to suffer before the red cells, and 
hence the type of anemia seen in the great majority of early cases 
resembles chlorosis. Fully normal Hb appears to be a good negative 
indication against carcinoma at any stage. In internal visceral car- 
cinoma this rule is almost invariable. There are, however, reports 
of 90 to 100 per cent, of Hb in cases with increased numbers of red 
cells, and the loss is doubtless slight during the early stages of most 
cases. In carcinoma of the breast there is often no sign of anemia. 
Usually a malignant epithelial tumor rather promptly reduces the 



MALIGNANT TU3I0RS. 423 

Hb, so that dariDg the greater part of its progress the Hb is below 
75 per ceut. From a comparison of results reported by various 
observers on about three hundred cases it appears that the averages 
encountered in routine experience are Hb 56 per cent., red cells 
8,700,000. In Bierfreund's and Eeinbach's series of fifty-seven 
surgical cases the Hb varied between 18 and 80 per cent., while few 
registered over 70 per cent., and in comparison with benign tumors 
the Hb in cancer was distinctly lower. After operation the restora- 
tion of the Hb required about a week longer with malignant than 
with benign tumors, and the restoration was never quite complete. 
With internal visceral carcinomata the Hb has usually been found 
even lower, but there are numerous exceptions to this rule, usually 
depending on the site of the tumor. 

A rather uniformly low percentage of Hb in visceral carcinomata was found 
by Laker, Eichhorst, Haberlin, Laache, Dehio, Leichtenstern, Moraczewsky, 
and Strauss and Rohnstein (40 per cent.), while Sailer's and Taylor's series of 
twenty-one cases gave the unusually low average of 25 per cent. Osterspey's 
and Cabot's cases were somewhat higher, often approaching the normal. Yet 
Haberlin concluded that in stenosis of the p>/lorus cancer is contraindicated if the 
Hb is over 60 per cent. In cases followed for considerable periods, as by Price- 
Jones, the Hb in some remained stationary, in others it declined, while in a 
single case (ovarian carcinoma) it remained normal for six months. 

The Hb-index is usually low. In some cases it has approached 
that of chlorosis, and although it is usually somewhat higher carci- 
noma offers a closer resemblance to chlorosis in this respect than 
almost any other cause of secondary anemia. As the disease pro- 
gresses the anemia itself becomes more severe, and when chronic 
cachexia has been long established the blood shows the characters of 
secondary pernicious anemia, with variations in the size of the cells 
and increasing Hb-index. Yet with rare exceptions the relatively 
great loss of Hb remains characteristic. 

Leichtenstern^ long since called attention to a rapid increase of Hb, to 100 
per cent, or more, seen in some cases of gastric cancer shortly before death, 
and to the tarry appearance of the blood at autopsy. Patrigeon, in a gastric 
case, found the red cells normal nine days before death. The writer has 
observed this condition in patients who had failed to take any food and little 
drink for some days before death. 

Special Factors in the Anemia of Carcinoma. The special con- 
ditions leading to severe anemia are numerous, and some are obscure. 
A previous condition of anemia may exist before the development of 
the cancer, as when a round ulcer of the stomach becomes malignant. 
The course of the blood changes in many cases strongly indicates 
i\i2ii i\iQ previous condition of the patient and the general constitu- 
tion are very prominent factors in the anemia of carcinoma. Hemor- 
rhage and ulceration are among the frequent complications recognized 
as rapidly impoverishing the blood, but occasional escape from their 
natural effects has been recorded. The site of the tumor may be such 
as to interfere with nutrition, as do some gastric carcinomata. 
Rapidly forming and numerous metastases are usually associated with 
severe and progressive anemia, but there are numerous exceptions to 



424 GENERAL DISEASES OF VISCERA, 

this rule, some emaciated subjects showing a tendency to concentra- 
tion of the blood. In two cases with extensive bone metastasis the 
writer found only moderate anemia and but few nucleated red cells. 
The histological character of the tumor appears to have no relation 
to the anemia except in so far as the structural type favors hemor- 
rhage or ulceration. The chronic toxemia of carcinoma may appar- 
ently affect the blood in a variety of ways. Miiller offers evidence 
to show that the blood of cancerous patients contains toxic principles 
which destroy albumins and diminish alkalescence. Grawitz injected 
the alcoholic extract of a cancerous tumor into rabbits, and, finding 
a considerable loss of gravity and dry residue, concluded that the 
toxins of carcinoma tend to dilute the blood by inducing excessive 
flow of lymph. 

Maragliano has demonstrated an increased glohulicidal activity of 
the serum in carcinoma. 

The Leucocytes. Leucocytosis in carcinoma Avas very early recog- 
nized as a frequent condition, having been observed postmortem by 
Andral, in 1823, and in the living blood by Lucke and by Yirchow 
about 1867. The white cells were long regarded as derivatives of 
the tumor, an error which was slowly relinquished when leucocytes 
were submitted to more careful classification by Schultze. 

That the carcinomatous process has in itself any capacity to draw 
leucocytes to the blood may still be doubted, although the edges of 
the tumor are always inflamed and adjacent lymph nodes invariably 
show inflammatory hyperplasia before metastasis. In tumors of 
ordinary size and character this inflammatory process is usually too 
limited to affect the leucocytes, but with very large growths, as in 
the liver, lung, uterus, etc., the frequency of leucocytosis without 
complications indicates that a large, actively growing tumor, merely 
through its local irritation, may induce leucocytosis. Thus Hayem 
saw a leucocytosis of 21,700 disappear after the removal of a scir- 
rhus of the breast, only to return again with the recurrence of the 
tumor. Hayem believes that recurrences may be predicted by the 
appearance of a gradually increasing leucocytosis. On the other 
hand, advanced cachexia may exist with hypoleucocytosis (Sailer, 
Taylor, Strauss and Hohnstein). Rapid growth is much more effect- 
ive in raising the number of leucocytes, probably by exciting more 
active local reaction, and by more sudden disturbance of function in 
the part affected. 

Superficial ulceration, or other inflammatory complications, are the 
usual causes of w^ell -marked leucocytosis with carcinoma. Hemor- 
rhages usually accompany ulceration, and add distinctly to the excess 
of leucocytes commonly seen in bleeding and ulcerating tumors. 

The type of the tumor has a distinct relation to leucocytosis, which, 
however, cannot always be traced. The cellular carcinomata tend 
to irritate, ulcerate, soften, and bleed, while fibrous tumors are of 
slow growth and non-vascular. The writer has observed two very 
large, gelatinous carcinomata of the peritoneum without leucocytosis. 
The diff'use cancers of the stomach regularly excite less increase of 
leucocytes than does the adenomatous type. 



3IALIGNANT TUMORS. 425 

The situation of the tumor often determines the frequency of leuco- 
cytosis from special liability to ulceration or bleeding. Many can- 
cers of the stomach and uterus illustrate this rule. Epithelioma of 
the esophagus rarely induces leucocytosis unless there is extreme 
ulceration and extension. 

Unusually high leucocytoses are reported in a case of carcinoma of thyroid, 
by Hayem, and in cases of unidentified tumors of the kidney, by Cabot, and 
in several cases of gastric cancer (q. v.). 

Leucocytosis in Cancer of the Breast. — Alexander found an average 
of 11,400 leucocytes, and variations between 2360 and 21 ,700, in fourteen cases of 
scirrhus. In three cases of alveolar carcinoma with extensive metastasis the 
leucocytes numbered 10,075, 11,625, and 12,400. Hayem (p. 947) found a dis- 
tinct reduction of leucocytes following four operations for scirrhus. The chief 
feature in the numerous counts of Price-Jones is the variability of the leuco- 
cytes in cancer of the breast. 

It will be seen that the leucocytosis of carcinoma is referable 
largely to complications, and these complications are such as appear 
very constantly in rapid or advanced cases. These conclusions 
accord with the general experience that most cases of well-established 
carcinoma are accompanied by leucocytosis. The great variety of 
these complications render it unwise to draw any narrow diagnostic 
conclusions from the presence or absence of leucocytosis. 

The varieties of leucocytes in the blood in carcinoma are found in 
much the same proportions as in other forms of cachectic leucocy- 
tosis. With marked leucocytosis the polynuclear cells usually form 
a high percentage, 77 to 89 per cent. (Keinbach) ; 74 to 96 per cent. 
(Cabot). Strauss and Rohnstein obtained an average of 15 per cent, 
of lymphocytes in thirty-five miscellaneous cases, and these authors 
believe that a relative diminution of lymphocytes is seen in the vast 
majority of anemic cases, proceeds uniformly with the disease, and 
without reference to the total number of leucocytes. Yet in a case 
of the pernicious anemic type of gastric cancer Sailer and Taylor 
reported 45,000 leucocytes, of which 46 per cent, were mononuclear, 
and these authors found the large mononuclear cells to regularly 
exceed the small lymphocytes. Unusually high leucocytoses have 
been reported in the anemic type of gastric cancer by several other 
observers, some instances of which apparently represent antemortem 
leucocytosis, while in others the excess was noted long before death. 
Eisenlohr, Mayer, and Lebert reported a ratio of 1 white to 50 red 
cells ; Potain, 1 to 48 ; Welch, 1 to 20. 

Braun has described a case of cancer of prostate with pernicious 
anemia (1,000,000 red cells, 10,700 leucocytes) in which the majority 
of white cells were lymphocytes, but a few eosinophile myelocytes 
were present. Eosinophiles usually persist in low normal proportions, 
from 1.2, 1.5, to 2 per cent. (Cabot, Sailer, Taylor, Reinbach). 

Myelocytes are found in a large proportion of cachectic cases, and 
sometimes in considerable numbers. They are most abundant in 
the antemortem leucocytoses, when the excess of various forms of 
leucocytes, with normoblasts and anemic red cells, may suggest 
leukemia. Sailer and Taylor found 9.3 per cent, of these cells in a 
very anemic case. Leucocytes holding fragments of red cells or 



426 GENERAL DISEASES OF VISCERA. 

showing various degenerative changes are described by Hayem and 
Escherich. 

Specific Gravity. The specific gravity of the blood in well-estab- 
lished carcinomatous cachexia is remarkably low. This fact is illus- 
trated in Dieballa's series, in which cases of gastric cancer with 
1,500,000 to 2,200,000 cells show the same gravity, 1.030 to 1.032, 
as cases of pernicious anemia with only 500,000 to 1,000,000 cells. 
Peiper also found very low gravity in four advanced cases, while the 
lowest reports are those of Moraczewsky, 1.012 and 1.016. While 
Hammarschlag obtained nearly normal gravity for the serum in 
these cases, Grawitz, Strauer, and v. Jaksch found exceptionally 
low percentages of dry residue and albumin, indicating that in car- 
cinoma the albumins of the serum suffer in a peculiar degree. 
Bieruacki located the marked loss of albumins principally in the 
red cells, but concluded that the iron is not always markedly dimin- 
ished. 

In the less advanced cases of carcinoma the gravity of the blood 
does not differ from that of other secondary anemias (Devoto, 
Schmaltz, Scholkoff, Hammarschlag, Stintzing, Gumprecht). 

The alkalescence of the blood has been found considerably dimin- 
ished, as in other forms of secondary anemia. Klemperer and 
V. Limbeck, Peiper and Rumpf, and Moraczewsky, using different 
methods, found very low grades of alkalescence in advanced cases. 
Van Noorden refers this change to the liberation of sulphuric, 
phosphoric, acetic, and oxy butyric acids, from the destruction of 
albumins. 

An excess of sugar was found by Freund in a series of cases, and 
while Trinkler confirmed these results, Matrai had previously showm 
that it is neither constant in nor peculiar to carcinoma. 

Hemolytic properties of the blood of carcinoma have been demon- 
strated by various observers. Strauss and Eohnstein found that a 
few injections of blood serum from such cases kill rabbits with a 
loss of 2,500,000 red cells and leucocytosis, maximum 23,200, and 
83 per cent, of polynuclear cells. Camus and Pagniez and others 
have found the serum of cancerous patients actively hemolytic for 
red cells of healthy subjects, while innocuous to the red cells of the 
patient. Bard and Milian have found the hemorrhagic fluids com- 
ing from pleural and peritoneal carcinomata hemolytic to normal 
human red cells. Lang finds that the hemolytic substance, while 
responsible for the anemia, leads to increased resistance in the 
remaining cells. 

A peculiar form of coma, described by v. Jaksch^ and others, some- 
times terminates the course of gastric cancer, and has been referred 
by Senator to an obscure toxemia resulting from disturbed metab- 
olism. Herter's demonstration of a great excess of bases over acids, 
and a great diminution of ammonia in the urine in chronic gastritis, 
strongly indicates that an acid intoxication exists in these cases, as 
in diabetic coma. (See Chronic Gastritis.) 



iMALIGXANT TUMORS. 427 



SARCOMA. 



The early changes in the blood in sarcoma closely resemble those 
of carcinoma, but some comparison of details will be of interest. 

Red Cells. The usual variations in the progress of anemia are to 
be observed, including the absence of oligocythemia, or even the 
presence of polycythemia in the early stages (Alexander, Reinbach, 
Cabot), and very slow or very rapid impoverishment of the blood 
according to the rate of growth and character of the complications. 

In the cases recorded by Hayem, Alexander, Laker, Limbeck, 
Sadler, Rieder, Reinbach, Bierfreund, Cabot, it is impossible to find 
any uniform difference in the grade of anemia from that observed 
with carcinoma, and this conclusion accords with the writer's experi- 
ence. Reinbach, however, finding only four normal blood speci- 
mens in twenty cases of sarcoma and six among sixteen cases of 
carcinoma, concluded that the anemia of sarcoma is usually greater 
than in carcinoma. 

There are also some pathological grounds on which Reinbach' s 
conclusions may be supported, in the special relation of sarcomatous 
growths to bloodvessels and marrow, their greater tendency to hemor- 
rhage and degeneration, and their more frequent association with 
febrile processes, leucocytosis, or even leukemia. 

The lowest number of red cells observed appears to be that 
recorded by Hayem at 663,400, while Rieder found only 6 per cent, 
of Hb (?) in a dying subject. Limbeck says that normal blood is 
more frequently found with early sarcomata than with early carci- 
nomata, while Reinbach has never seen in early carcinoma the 
extreme alterations of the blood which he referred to an early sar- 
coma. Alexander reports an extensive osteosarcoma of sternum and 
vertebrae with over 6,000,000 red and 52,000 white cells, and in his 
and other series of osteosarcoma the average anemia is not extensive. 

In Cabot's sixteen cases the average of red cells was 4,400,000, 
with extremes between 2,600,000 and 6,200,000. 

Nucleated red cells are rather less common than in carcinoma. 
The changes of progt^essive pernicioiis anemia were present in the 
blood in cases of osteosarcoma reported by Grawitz, Ehrlich, Mosler 
and Gast, Fede, and Hausler. 

Leucocytes. The relatively greater frequency and extent of leuco- 
cytosis in sarcoma appears to be the most striking difference in the 
blood between the two groups of malignant tumors. The great 
majority of sarcomata when first observed have shown a distinct 
leucocytosis, which, moreover, tends to persist and often to increase, 
with the advance of the tumor, until at death the upper limits of 
inflammatory leucocytosis are frequently reached. Martin and Mat- 
thewson have described leucocytosis of this extreme type and pointed 
out some of the difficulties in diagnosis which may result therefrom. 

Indeed, there are several recorded instances in which the lympho- 
cytosis of sarcoma terminated in lymphatic leukemia. The writer 
observed such a case in 1899, and others have been reported by 
Raima, Sadler, and Strauss. 



428 GEXERAL DISEASES OF VISCERA. 

Palma's and Sadler's cases were round-celled sarcomata. In the writer's 
case various parts of the tumor and its metastases showed gradations between 
round and large spindle-celled sarcoma. The recorded transformations of 
pseudoleukemia into leukemia are doubtless of similar significance (Fleischer, 
Penzoldt, v. Jaksch,^ Westphal, Mosler, Senator). 

The types of leucocytes show greater variety in sarcoma than in 
carcinoma. The majority of leucocytoses being of inflammatory 
origin, an excess of polynuclear cells is the rule, and even with a 
normal number the proportion of these cells may be excessive. 
Lymphocytosis, though not relatively frequent with sarcomata, 
has at times reached the grade of lymphatic leukemia, as in the cases 
mentioned. In lymphosarcoma, as in pseudoleukemia, the lympho- 
cytes are not usually excessive, and in many cases are very scanty. 
EosixoPHiLiA has been regarded by Xeusser as one of the diagnostic 
signs of sarcoma of bone-marrow. A marked and persistent excess 
of these cells, 48 per cent., was found in one of Eeinbach's cases of 
lymphosarcoma complicated by phthisis, and bone metastases were 
found at autopsy. Three other cases, without autopsy, showed 
from 8 to 12 per cent, of eosinophiles, but these cells were normal in 
most of his cases, and absent in five. 

There seems to be some difference in the extent of leucocytosis 
observed in various types of sarcoma. In sixteen cases of osteosar- 
coma collected by Cabot from several authors the average was 
17,000, in twelve lymphosarcomata 20,000, and in seven melanotic 
sarcomata 25,100. AMthout further details than the reports of these 
cases furnish, the significance of these data is limited. The greater 
leucocytosis of melanotic sarcoma accords with its recognized malig- 
nancy, and some marked leucocytoses observed by Alexander and 
Limbeck (52,000 and 32,000) in osteosarcomata may perhaps go 
with myeloid tumors, which are more malignant than the periosteal. 

Myelocytes were noted in Reinbach^s case, cited above, which also 
showed eosinophilia. Cabot found 7 per cent, of large and small 
myelocytes in a case of general sarcomatosis, and an occasional 
myelocyte in three other cases. 

Bibliography. 

Cancer, Sarcoma. 

Alexander. These de Paris, 1887. 

Andral. Ai'chiv gen. de Med., June, 1823. 

Bard. Cited bj^ Menetrier. 

Bierfreund. Langenbeck s Archiv, Bd. 41, p. 1. 

Biernacki. Zeit. f. phvsiol. Chem., Bd. 19. 

Braun. Wien. med. Woch., 1896, pp. 482, 582. 

Daland. Fort. d. Med., 1891, Xo. 20. 

Dehio. St. Petersb. med. AVoch.. 1891, p. 1. 

Devoto. Zeit. f. Heilk., 1891, p. 176. 

Diehalla. Deut. Arcliiv klin. Med., Bd. 57, p. 302. 

Ehrlich. Charite-Annalen, 1878, Bd. 5. 

Eichhorst. Spec. Path. u. Therap., Bd. 2 

Eisenlohr. Deut. Archiv klin. Med., Bd. 20, p. 495. 

Epstein. Wien. med. Presse, 1894, p. 2050. 

Escherich. Berl. klin. Woch., 1884, p. 145. 



3IALIGXAXT TUMORS. 429 

Fede. Cited bv Ehiiich, Charite-Annalen, Bd. 5. 

Fleischer, Penzoldt. Deut. Archiv kliii. Med., Bd. 26, p. 368 

Freund. Cong. f. inn. Med., 1889. 

Grawitz. ^Virchow's Archiv, 1876, p. 323: 

HaherUn. Mlinch. med. Wocli., 1888, No. 22. 

Hammarschlag. Zeit. f. klin. Med., Bd. 21. 

Hampeln. Cited by Neubert. 

Hausler. Diss. Greifswald, cited bv Miiller. 

Herter. Trans. N. Y. Path. Soc, 1900. 

V. Jaksch. 1 Wien. med. Woch., 1883, pp. 473, 512. ^ Zeit. f. Idin. Med., Bd 6 
p. 423. 

Klemperer. Charite-Annalen, Bd. 15, 1890. 

Laache. Die Anaemie, 1883. 

Laker. AVien. med. Woch., 1886, Nos. 18-20. 

Lang. Zeit. f. klin. Med., Bd. 47, p. 153. 

Lebert. Krankh. d. Magens. Tubingen, 1877, p. 481. 

Leichtenstern. ^ Unters. u. d. Hb-gehalt., etc., Leipzig, 1878. ^Ziemssen's 
Handb., Bd. 8, p. 344. 

Martin, Matthewson. Brit. Med. Jour., 1896, ii. p. 1634, 

Matrai. Pest. med. chir. Presse, 1885. 

Mayer. Aerzt. Intelligensbl., 1870, No. 21. 

Milian. Tumeurs et Cytohemolyse, Soc. Anat., 1901. 

Moraczewsky. Virchow's Archiv, Bd. 114, p. 1.27. 

Mosler. Virchow's Archiv, Bd. 114, p. 461. 

Mosler, Gast. Deut. med. Woch., 1885. 

Mouisset. Revue de Med., 1891, p. 885. 

F. Muller. Zeit. f. klin. Med., Bd. 16. 

Neubert. Inaug. Diss. Dorpat, 1899. St. Petersb. med. Woch., 1889, No. 32. 

Van Noorden. Lehrb. d. Path. d. Stoffwechsels., p. 461. 

Osterspey. Berl. klin. Woch., 1892, pp. 271, 308. 

Pagniez. These de Paris, 1902. 

Palma. Deut. med. Woch., 1892, p. 784. 

Patrigeon. These de Paris, 1877. 

Peiper. ^ Cent. f. klin. Med., 1891, p. 217. ^ Virchow's Archiv, Bd. 116, p. 337. 

Potain. Gaz. d. Hop., 1888, p. 525. 

Price-Jones. Middlesex Hosp. Rep., 1902, vol. i. p. 113. 

Reinbach. Langenbeck's Archiv,' Bd. 46, p. 486. 

Rumpf. Cent. f. klin. Med., 1891, p. 441. 

Sadler. Fort. d. Med., 1892; Suppl. Sept., p. 38. 

Sailer, Taylor. Internat. Med. Mag., vol. vi. p. 404. 

Schmaltz. Deut. Archiv klin. Med., Bd. 47, p. 145. 

Scholkoff. Diss. Bern, 1892. 

Senator. Berl. khn. Woch., 1882, No. 19. 

Stintzing, Gumprecht. Deut. Archiv klin. Med., Bd. 53, p. 265, 

Strauer. Inaug. Diss. Greifswald, 1893. 

Strauss. Charite-Annalen, 1899. 

Strauss, Rohnstein. Blutzusam b. d. verschied. Anaemien, BerHn, 1901. 

Trinkler. Cent. f. med. Wissen., 1890. 

Welch. Pepper's Syst. Med., vol. ii. p. 552. 

Westphal. Diss. Greifswald, 1887. 



PART VI. 
ANIMAL PARASITES. 



CHAPTER XXIII. 

MALARIA. 
I. TECHNIQUE. 

(a) The Examination of Fresh Blood. By far the readiest 
method of determinmg the presence of malarial infection is by the 
examination of the fresh blood. For this purpose thoroughly cleaned 
and polished slides and cover-glasses are the chief requisites, and a 
thin layer of blood may be secured by touching the exuded drop to 
the cover-glass, which is immediately laid upon the slide and examined 
with a one-twelfth immersion lens. The quantity of blood should 
be small, and in the resulting layer the red cells should be separated 
from each other. Besides the facility in preparation, this method 
permits the study of the vibratory motion of pigment, of ameboid 
motion of the parasite, of some limited phases of the natural devel- 
opment of the parasite, such as exflagellation, and of some artificial 
changes, such as the escape of the parasite from the cell, and occa- 
sionally of the formation of vacuoles. 

By mixing the blood with ascitic fluid deeply tinged with methy- 
lene blue, Celli and Guarnieri secured excellent stained specimens 
of the parasite in the fresh condition. The ascitic fluid was pre- 
pared by dissolving powdered methylene blue in the fluid and filter- 
ing. The blood was mixed with this fluid and spread under a 
cover-glass in the usual way. Their drawings of parasites seen 
under these conditions appear to have been the first definite repre- 
sentation of the nuclear body of the malarial organism. Xo other 
notable modification of the method of examining malarial blood in 
the fresh condition appears to have been perfected. 

Concerning the value and reliability of these methods opinions 
are somewhat at variance. Most of the early study of malarial 
blood was made exclusively by this method, and it still remains, of 
course, the only method, permitting the minute study of many 
important changes in the form of the parasite, of the motility of the 
pigment, and of some degenerative processes. On the other hand, 
exclusive reliance on this method appears to have been responsible 



432 ANUIAL PARASITES. 

for much confusion regarding the varieties of the parasite and its 
minute structure, as well as for many erroneous interpretations of 
exceptional or artificial changes in the organism. 

As a ready means of diagnosis, in the hands of an expert, the 
examination of fresh blood is all that is required in the average case, 
and when the parasites are moderately numerous and when crescents 
are present, even an inexperienced observer can hardly err. Under 
any other conditions, except for special purposes, reliance upon this 
method appears to the writer iuadvisable. When the parasites are 
scarce, especially when they are of the small, unpigmented form, a pro- 
longed search through fresh blood has frequently proven negative, 
in the writer's experience, although a few minutes sufficed for the 
discovery of one or more minute parasites in the stained specimen. 
Practically, this fact demands that a negative result with a fresh 
specimen be invariably controlled by the examination, with mechani- 
cal stage, of a stained specimen. Moreover, anyone who is familiar 
with the host of appearances in fresh blood simulating the malarial 
parasite must regard with some suspicion the report, from anyone 
but a recognized expert, of the discovery of one or two ^^ hyaline 
bodies. '^ From these considerations the writer would limit the use 
of fresh specimens to the study of a few special features of malarial 
parasites, and would urgently recommend that as a diagnostic pro- 
cedure reliance be placed only upon the examination of dry specimens 
stained, preferably, by Nocht's method. 

The study of flagellate bodies may be conducted in fresh specimens 
prepared in the ordinary way, but placed, if possible, on a warm 
stage. Mannaberg alone claims to have found the flagellate bodies 
in considerable numbers in the fresh human blood immediately after 
shedding. Usually they appear only after the lapse of ten to twenty 
minutes, when they may form in variable numbers from the larger 
tertian or crescentic estivo-autumnal organisms, less frequently from 
quartan parasites. 

The addition of a little water or salt solution may facilitate the 
escape of the parasite from the red cell and the formation of flagella. 

The successful action of moisture has been obtained by several 
expedients. Marshall added about an equal quantity of water to a 
small drop of blood containing many crescents and saw the almost 
immediate change of crescents to spheroidal bodies, followed by 
exflagellation. Manson recommends that the blood under the cover- 
glass be kept moist by exposure to steam exhaled from a hot moist 
sponge. After a few minutes the cover may be carefully removed, 
the specimen dried, and the flagellate bodies stained. 

The writer finds that the moist chamber may be secured in a Petri 
dish with tightly fitting vaselined cover. Wet blotting paper placed 
in the dish furnishes the necessary moisture. Specimens spread on 
slides or covers may be kept moist for ten to twenty minutes in such 
dishes, and flagellation proceeds with moderate rapidity. 

A simple method is as follows : Cut an opening J x 1 inch in a 
piece of thick blotting paper and moisten the paper in hot water. 
Spread two glass slides rather thickly with fresh blood, lay the 



MALARIA. 433 

blotting paper on one slide, cover the cut opening by the other, 
specimen side down, and slip a rubber band about both. After 
fifteen to twenty minutes the slides and paper may be separated and 
the two specimens dried. 

Far more important than any of these details is the stage of the 
infection in which the patient is found. No amount of manipulation 
will succeed in inducing the changes of exflagellation in parasites 
wdiich are not capable of them. In the early paroxysms of initial 
infections attempts to obtain flagellate bodies almost always fail, 
while in the late stages of relapsing cases with rich infection, in 
which the sexes of the parasite have become differentiated, flagellate 
bodies form readily and in large numbers. 

(6) Preparation of Dry Specimens. Smears of the blood may 
be prepared by any of the usual methods. After drying thoroughly 
in the air the malarial parasite stains best after fixation in 95 to 97 
per cent, alcohol for fifteen to thirty minutes. Five minutes' fixation 
will suffice, but if left in alcohol over night the staining qualities 
of the organism will sometimes be found slightly altered. When 
slides have been kept in alcohol, or in the air, after fixation by heat 
or alcohol, for periods varying from one month to three years, there 
is a progressive loss of the capacity to unite with eosin, while methy- 
lene blue gives a deep, diffuse stain. This tendency may be gradu- 
ally corrected by passing the slides rapidly through a y^ per cent, 
solution of nitric acid. 

Fixation by heat is less satisfactory for the present purpose, and 
the addition of ether to the alcohol secures no advantage. 

Staining Methods. Eosin and Methylene Blue. S'or ordinary 
purposes staining by eosin and methylene blue may be generally 
recommended, and many of the detailed studies of the parasite have 
been based upon specimens stained in this way. The solutions 
required are : (1) a saturated alcoholic solution of Ehrlich\s blood 
eosin, diluted with an equal quantity of 95 per cent, alcohol or a 1 
per cent, solution in water of Griibler's yellow, water-soluble eosin, 
and (2) a saturated watery solution of Ehrlich's rectified methylene 
blue at least one week old. 

A light staining by eosin, such as is given by the diluted solution 
of eosin, is essential for the clear demonstration of the parasite by 
methylene blue, and in specimens containing only the small signet- 
ring forms, heavy staining by eosin may almost entirely prevent the 
subsequent action of methylene blue, and these minute parasites may 
be overlooked. 

By intense staining with old solutions of alcoholic eosin which 
have absorbed water, fragments of the red cell probably containing 
traces of Hb may often be demonstrated in the meshes of the para- 
site, of the presence of which no indication is given by the usual 
method. 

Methylene blue fails to stain the young ring forms, especially of 
the tertian type, as clearly as is desirable, and more powerful basic 
staining fluids may well be employed for this purpose. Nocht's 
method may be recommended over any other, as it facilitates the 

28 



434 ANIMAL PARASITES. 

identification of the small rings by means of a large, densely stained 
nucleus, but when this method cannot be employed one may resort 
to the method modified by Futcher and Lazear from the suggestions 
of Benario and of Marchoux, as follows : 

"Fix the specimens five minutes in 95 per cent, alcohol, to 
100 c.c. of which has been added 1 c.c. of formalin. Stain one to 
three minutes in the following mixture: saturated alcoholic solution 
thionin, 20 c.c. ; 20 per cent, carbolic acid, 100 c.c. The fixing 
solution must be used fresh, and the staining fluid must be at least 
one week old. The rings are then densely stained and the speci- 
mens do not fade.^^ 

The sharpest demonstrations of minute, ring-shaped parasites 
secured by the writer were obtained by staining one hour in diluted 
Gage's hematoxylon before treatment by eosin and methylene blue. 
Hematoxylon stains the nucleus of the ring and makes the body of 
the parasite blacker after methylene blue. Such specimens are 
specially suitable for photography. 

The Nocht-Romanowsky Method. The method originally devised 
by Romano vvsky, and which has given such uncertain results in the 
hands of many investigators, has now been modified most success- 
fully by IN^ocht, whose procedure gives positive results without 
much dependence upon the quality of dyes or the time of staining. 
(The interesting history of this stain may be found in the writer's 
article on '^Malarial Parasitology," Journal of Experimental Medi- 
cine, 1901.) 

Nocht's modification consists in the addition of a few drops of 
neutralized Unna's polychrome methylene blue (Griibler) to the 1 
per cent, solution of ordinary methylene blue. The usual specimen 
of polychrome methylene blue is distinctly alkaline, and to be ren- 
dered effectual for the present purpose Nocht found that it requires 
neutralization, preferably by acetic acid. This may be done by 
adding drop by drop of dilute 2 to 3 per cent, acetic acid until the 
commercial fluid polychrome blue no longer turns red litmus blue 
above the zone coming into immediate contact with the dye. The writer 
has never failed to secure a good result by the following procedure : 

1. To one ounce of polychrome methylene blue (Griibler) add five 
drops of 3 per cent, solution of acetic acid (U. S. P., 33 per cent.). 

2. Make a saturated 1 per cent, watery solution of methylene 
blue, preferably Ehrlich's (Griibler) or Koch's, dissolving the dye 
by gentle heat. This solution improves with age, and should be at 
least one week old. 

3. Make a 1 per cent, watery solution of Griibler's watery eosin. 
The mixture is prepared as follows : 

To 10 c.c. of water add four drops of the eosin solution, six drops 
of neutralized polychrome blue, and two drops of 1 per cent, methy- 
lene blue, mixing well. The specimens, fixed in alcohol, or by 
heat, are immersed, specimen side down, for one lo two hours, and 
will not overstain in twenty-four hours. The density of the blue 
stain may be varied to suit individual preferences. The above pro- 
portions need not be rigidly followed, but the polychrome solution 



3IALAEIA. 435 

should be accurately Deutralized, and the staining mixture should be 
deep blue. 

Nocht later reports that the two soliitious of rn ethylene blue may 
be replaced by a 1 per cent, solution of Ehrlich's methylene blue, 
alkaliuized by J per cent, of NaOH and kept a few days in a ther- 
mostat at 50° C. This is the ordinary laboratory method of impro- 
vising polychrome methylene blue. To 2 c.c. of water add two to 
three drops of 1 to 2 per cent, watery eosin, and drop by drop of the 
alkaliuized methylene blue until the original red color of the eosin 
has almost disappeared. In this fluid specimens stain in five to ten 
minutes. This method is less reliable than the former. 

The rationale of the Xocht-Romanowsky method is not yet fully understood, 
but it appears most probable that a staining agent which unites selectively 
with chromatin exists ready formed in polychrome methylene blue, and may 
be developed in specimens of methylene blue in various ways, among which 
is slow digestion with an alkali and heat. Nocht refers to this principle as 
" red from methylene blue." It may be extracted from polychrome methylene 
blue, etc., by chloroform (Nocht). Michaelis describes its relations to methylene 
blue, and calls it " methylene azur." It can be obtained from Griibler under 
the name of '' azur-blau," and may be employed in the following watery mix- 
ture recommended by Laveran : 0.1 per cent, eosin, 2 parts; aq. dest., 8 parts; 
1 per cent, azur II., 1 part. Wash in water and then in 5 per cent. sol. tannin. 

Goldhorn has succeeded in digesting methylene blue with saturated solution 
of lithium carbonate so as to develop in it a large proportion of the red chro- 
matin-staining principle. This fluid, neutralized by acetic acid, not only stains 
the chromatin rapidly (fifteen to sixty seconds), but demonstrates, better than has 
yet been done, early and extreme granular degeneration of the infected and other 
red cells. Goldhorn's blood stain in methyl alcohol fi.xes and stains at the same 
time, and may be procured from New York dealers. (See Transactions New 
York Pathological Society, February, 1901. 

One who wishes to make the stain himself from methylene blue should fol- 
low the directions given by Wright. 

Nocht's method furnishes so much information regarding the 
minute structure of the parasite, and renders its identification so 
complete and positive, that it must be recommended above all other 
methods of staining the malarial parasite. Moreover, it has a large 
field of application in the study of nuclear structures in various other 
micro-organisms. 

II. MORPHOLOGY. 

The Tertian Parasite. 1. The youngest form of the tertian para- 
site seen in the red cell is identical in appearance wdth the spore of 
the parent rosette. It is a compact, spheroidal or slightly oval, or 
irregular body, about ^ji in diameter. It shows an outer rim of 
basophilic protoplasm inclosing a single large nuclear body which is 
achromatic to methylene blue, but stains readily in hematoxylon or 
by Nocht^s method, and which is usually enclosed or accompanied by 
a clear achromatic substance or space, termed by Gautier " the milky 
zone.'' (Plate XIY., Fig. 1.) 

In the fresh condition these bodies are noticeably refractive, espe- 
cially the nucleus, change their position but rarely their shape, and 
are never pigmented. From the earliest period of infection the red 
cell is often swollen. 



436 ANIMAL PARASITES. 

2. The Young Tertian Ring. Within a few hours after the chill 
the parasite is usually found to have assumed a somewhat character- 
istic ring sliape, which it commonly maintains in some definite form 
up to the pre-segmenting stage. In the late stages of the infection 
many young tertian parasites do not assume the ring form, but 
remain compact. (Plate XVIII., Fig. 4.) It seems probable that 
these forms develop into male flagellating bodies. 

These (ring-shaped) bodies measure from Zfi to 4/i in diameter, 
and the regular ring form is retained without marked increase in 
bulk at any point for six to eight hours. Sometimes the ring is 
elongated, one arm reaching across the cell, while a thin bow per- 
sists. Occasionally the ring appears to unfold, and the parasite 
stretches clear across the swollen cell, with the nucleus at one end. 
The tertian ring is rarely as geometrical or delicate as the estivo- 
autumnal signet-ring. The development of pigment is inconstant, 
some large rings failing to show pigment, but usually one or more 
fine grains are to be seen in the medium-sized and smaller forms. 
The ring always encloses a considerable mass of hemoglobin. The 
nuclear body of the tertian ring is its most characteristic feature, 
appearing as a rather large, achromatic, highly refractive body after 
methylene blue, but staining intensely with hematoxylon and by 
Nocht^s method. 

Significance of the Ring Form. — In regard to the formation and signifi- 
cance of the ring, opinions are at variance. Most of the Italian writers hold 
that the ring form is not really a ring, being bridged across by a transparent 
and vesicular nucleus. There are many considerations favoring this view, 
especially the usual appearance of the parasite in the fresh condition, and 
the fact that the chromatin usually lies within the ring, eventually filling it. 
On the other hand, Mannaberg and Ziemann claim that this body is a true 
ring, formed by the thinning of the central portion of the body of the para- 
site, and state they have seen the ring develop in this manner in the fresh 
blood. From the examination of the rings themselves the writer has been 
unable to convince himself as to which view is correct, but there are some 
early forms of the parasite which strongly indicate that the ring does not 
represent a vesicular nucleus. In one such form the ring is unfolded and the 
nuclear body of the parasite lies naked in the hemoglobin. Moreover, elon- 
gated forms of the young parasite are often seen in which the ring is absent 
and the nuclear body lies bare at one end. These forms vividly recall the 
appearance of the ameha dysenterice in which the nucleus remains at the hinder 
end during active movements of progression. Further, it is difficult to asso- 
ciate the relatively huge size of the ring with any nuclear structure, which 
would require the young malarial parasite to have a nucleus which is larger 
than that of the adult ameba dysenterice. Again, secondary rings sometimes 
form from the union of pseudopodia, and these are identical in appearance 
with the primary ring, but lack the chromatin granules. 

In specimens stained by Nocht's method the chromatin is usually found 
within the ring, sometimes lying in an isolated position in the centre, but 
very often the chromatin is found outside of the ring, connected by a very 
fine thread of protoplasm. If the ring represents a vesicular nucleus, we 
have here the anomaly of a complete separation of chromatin from the vesicu- 
lar portion of the nucleus, which is opposed to some rigid histological princi- 
ples. Even more frequently the chromatin is found to be enclosed by bluish 
stainina: protoplasm which shuts it off" entirely from the ring. (Plate XIV., 
Fig. 7.) 

From various biological studies it appears that the nuclei of the protozoa 
are usually widely different from the nuclei of metazoa. Many protozoa do 



PLATE XIV 







cy ^^ - 



















Developmental Cycle of Benign Tertian Parasite. 

Fig. 1. Very early form of parasite, showing chromatin grannie, " milky zone," and spheroidal 

body. 
Figs. 2, 3. Typicar young ring-shaped parasites. 
Figs. 4, 5. Subdi^dsion of chromatin, development of body, and appearance of pigment in later 

ring-forms. 
Fig. 6. Double rings in single parasite. 

Figs. 7, 8. Turban-shaped parasites. Secondary rings, eccentric position of chromatin. 
Fig. 9. Double infection of cell. 

Figs. 10, 11. Complex ameboid figures in doubly infected cells. 
Fig. 12. Full-grown form, with large eccentric nucleus. 
Figs. 13, 14. Protrusion of chromatin granules and milky substance in botly of fiill-growu 

parasite. 
Figs. 15, 16. Division of chromatin granules into groiips in reticulated pn^segmenting bodies. 
Fig. 17. Tertian rosette. 



MALARIA. 437 

not have a vesicular nucleus, with cell membrane, linin, nucleolus, etc., but 
possesses the so-called " distributed nucleus ^^ composed of a number of granules 
lying free in the body of the parasite. The study of the malarial parasite by 
Nocht's method indicates that the nucleus of this protozoan is of the dis- 
tributed type, which does not exhibit a vesicular appearance nor possess a 
nuclear membrane. (See Calkins on " Protozoan Nuclei," Annals Neiu York 
Academy Sciences, 1898, vol. ix., part iii.) On these grounds the writer is 
inclined to agree with Mannaberg and others who hold that the form in ques- 
tion is a true ring, a form usually but not necessarily assumed by the parasite, 
and does not represent a vesicular nucleus. 

Marchiafava and Bignami still hold that the ring is bridged over by an in- 
visible membrane. They do not insist, as do many, that this membrane is a 
nuclear structure, but consider the central area to be a digestive vacuole. 

Comparison of the Tertian and Estivo -autumnal Rings. From the 
study of the ring-shaped tertian parasite and the estivo-autumnal 
signet-ring forms, in typical cases of these infections, the writer 
believes that these parasites, with very rare exceptions, can be fully 
distingaished from each other in this early stage, and on the follow- 
ing peculiarities : 

1. The nuclear body and chromatin mass of the young tertian 
parasite is achromatic to methylene blue, which densely stains the 
nucleus of the estivo-autumnal organism. The writer has been 
unable to find in the literature any specific reference to this diag- 
nostic peculiarity, which may be readily verified by comparing 
specimens of the two parasites stained by methylene blue and by 
Nocht's method. 

The dense staining by methylene blue of a nuclear body in the young estivo- 
autumnal parasite has often been noted, and in 1894 Okintschitz mentioned 
the fact that the nucleus of the young tertian parasite fails to stain by methy- 
lene blue. 

2. The shape and contour of the tertian ring is usually coarse 
and irregular, but the estivo-autumnal ring is geometrically circular, 
more delicate, with an extremely fine bow, and usually with a typical 
signet-like swelling. (Plate XIY., Figs. 2, 3, and Plate XTVl., 
Figs. 6, 7.) . . 

3. One or two grains of pigment are almost invariably found in 
the early tertian ring, but are, with nearly equal constancy, absent 
from the estivo-autumnal signet-ring. 

4. The writer's specimens confirm the statement of Gautier that 
the tertian ring is usually pigmented before the chromatin becomes 
subdivided, while the chromatin of the estivo-autumnal ring is 
always subdivided before the appearance of pigment. In some 
cases, however, the chromatin of the tertian ring divides before 
pigmentation. 

5. The infected cell is usually swollen from the moment of infec- 
tion by the tertian spore, and commonly shrunken when harboring 
the estivo-autumnal ring. 

All of these characters are usually apparent in ordinary speci- 
mens, but naturally are most distinct in flatly spread and rapidly 
dried cells. The writer has met with no exceptions to the above 
rules in cases infected by the tertian parasite in New York and cases 
of estivo-autumnal infection from Cuba. In many of the irregular 



438 AXUIAL PARASITES. 

relapses, in cases showing tertian organisms, encountered among 
volunteer soldiers long returned from Cuba, single, ring-shaped para- 
sites not admitting of positive identification have sometimes been seen. 

3. Large Tertian Rings. After a period of six to eight hours the 
tertian ring is usually found to have developed an outgrowth which 
is activelv ameboid in the fresh condition, and appears in stained 
specimens as a tongue-like protrusion or turban-shaped mass attached 
to one segment of the ring. (See Plate XIV.) The nuclear body 
meanwhile increases slightly in size, projecting into the ring, and 
the chromatin divides into several large granules. 

At this period occurs the greatest ameboid activity of the parasite, 
and in some severe tertian infections the organism may be found 
fixed in the height of its ameboid excursions, when it presents in 
stained specimens the peculiar appearance depicted in Plate XI Y., 
Figs. 9 and 10. There the ring persists, but the body of the para- 
site is strung out into a number of slender threads with nodal thick- 
enings. At times, especially in cases taking quinine, the number 
and delicacy of the threads greatly exceed those seen in the sketch, 
which represents an average instance. 

A close inspection of cells harboring such parasites may disclose 
the presence in one cell of two distinct nuclear bodies, indicating 
the co-existence of two parasites. Frequently twin |)arasites entirely 
separate from the other are found in the same cell, each of which 
shows a tendency to develop the long threads. (See Plate XIV., 
Fig. 9.) When, however, the threads are numerous and very thin 
it is usually impossible to find any break in their continuity, while 
in many instances the two parasites are distinctly united. The 
significance of these forms will be considered later. (See Conjuga- 
tion.) 

4. Tertian Spheroidal Bodies. During the second quarter of the 
cycle the body and the nucleus of the parasite develop rapidly in 
size, ameboid motion and ameboid figures gradually diminish, and 
pigment is abundantly deposited in the form of fine dark-brown or 
yellowish grains showing in the fresh state active vibratory motion. 
The infected cell continues to increase slightly in size, and its hemo- 
globin is progressively diminished. 

Depending upon the character of ameboid activity, the variety of 
figures seen during this period is very great. Eventually, toward 
the end of twenty-four hours or possibly somewhat later, the parasite 
occupies three-fourths of the swollen cell, in the form of a spheroidal 
or elliptical, hotiiogeueous body, the outer portion of which contains 
most of the pigment and is rather more deeply stainable than the 
zone immediately surrounding the nucleus. (Plate XIV., Fig. 12.) 
The nucleus gradually increases in size, growing into the ring. It 
no longer has the appearance of a small, highly refractive, achromatic 
spot (after methylene blue), but takes a light bluish tinge with 1 
per cent, methylene blue, and stains less deeply than before with 
hematoxylon. At the end of this period the nucleus completely fills 
the ring, stains rather distinctly with methylene blue, and sometimes 
exhibits a delicate bluish network. 



3rALARIA. 439 

After Nocht's method the changes in the nucleus are found to consist in the 
gradual subdivision of the chromatin granules, which finally become rather 
numerous, of minute size, and more difficult to stain. 

Usually these chromatin granuleslie on the inner circumference of the bow 
of the ring, projecting within the ring, and partly surrounded by a " milky,'' 
unstained space. This clear zone is often absent in young parasites in cells 
thinly spread and rapidly dried, but in older parasites it is always present. 
Various other positions may be assumed by the chromatin mass, as follows: 

A subdivision of the granules into two distinct groups, separated by a strand 
of bluish-stained protoplasm ; an excentric position entirely apart from the 
ring; a position midway between two rings found in the same parasite ; a posi- 
tion in the centre of the ring entirely apart from any bluish protoplasm ; a 
circular arrangement about the periphery of the ring. Sometimes the smaller 
granules are grouped about a central, larger granule, as has been noted in 
other protozoa whose nuclei are of the intermediate type {Microglena, 
Euglena). (Plates XIV., XVI. ) 

5. Full-grown Tertian Parasites. The third quarter is occupied by 
the continued growth of the parasite in the form of a large, homo- 
geneous, richly pigmented body, which finally occupies at least four- 
fifths of the swollen cell, and by certain nuclear changes which it is 
difficult to follow in specimens stained by methylene blue or heraa- 
toxylon, but are fully demonstrated by Nocht's method. The exact 
limits within which the parasite may be termed ^' full grown'' can 
be sharply fixed only with great difficulty, but there appears to be a 
period of at least twelve hours during which there is little change 
in the structure of the organism, and during which the body stains 
homogeneously and the nucleus occupies the entire ring. The writer 
would place this period between the twenty-fourth and fortieth hour 
of the cycle. A portion of the period is occupied by nuclear changes 
belonging to the reproductive phase of the parasite's development. 

After the appearance of a faint intranuclear network most authori- 
ties agree that the nucleus largely disappears in specimens stained 
by methylene blue or hematoxylan, and is next seen in the form of 
highly refractive achromatic spots in the meshes of the reticulated 
pre-segmentinc>' body (methylene blue), and these again stain deeply 
with hematoxylon. 

Nocht's method, however, fully demonstrates the nuclear changes which 
occur in the full-grown parasite. A considerable area, usually the entire 
original^ ring, is now occupied by a " milky " or slightly bluish staining sub- 
stance, in which lie a considerable number of very fine chromatin granules. 
These granules are usually difficult to stain, and being of very minute size 
they are difficult to see. This fact has led Ziemann and Gautier to admit 
the possibility that the chromatin may actually disappear at one stage of the 
development, especially since they have found some large parasites in which 
no chromatin was demonstrable. In the writer's specimens there were a 
very few large tertian parasites in which no chromatin granules appeared, 
but these were not more numerous than younger forms which were devoid 
of chromatin and which must, therefore, be regarded as sterile. Similarly, 
the larger forms devoid of chromatin the writer would class with the sterile 
forms rather than accept the view that the chromatin may entirely disappear 
at one stage of the fertile parasite, a view which is at variance with biological 
principles. After the subdivision of chromatin has reached a limit, the next 
change, observed in a considerable number of parasites, appears to consist in 
the extrusion of a portion of the milky stibstance and its chromatin granules 
into the body of the parasite. (Plate XIV., Fig. 13.) At the same time the 
granules of chromatin increase in size and diminish in number. Other 



440 ANIMAL PARASITES. 

forms may be seen in which the " milky substance" and chromatin granules 
occupy an elongated space within the body of the parasite, and in such 
cases the beginning concentration of pigment and deeper stain of the parasite 
indicate the presence of the pre-segmental stage. (Plate XIV., Fig. 14.) 

Considerations pointing to the subdivision of the group of full-grown tertian 
parasites are mentioned in the section on Conjugation. 

6. Pre-segmenting bodies usually begin to appear in the blood eight 
to ten hours before the chill. 

In specimens stained by methylene blue the first demonstrable 
indications of the division of the parasite are seen in a deeper staining 
capacity and tendency toward reticulation which appear throughout 
the whole or in a part of the body of the parasite. Occasionally 
these changes may be noted in one-half the parasite, while the other 
half retains the homogeneous apperance of the ^^ full-grown " organ- 
ism. Usually the process is found to have affected the entire 
organism, giving the very characteristic forms sketched in Plate 
XIV., Figs. 15 and 16. In the pre segmenting bodies the pigment 
is gathered in a reduced number of coarse grains or spindles which 
lie in the body of the parasite, in a position determined by that of 
the new multiple nuclei. 

These bodies were first described by Golgi in fresh blood and properly in- 
terpreted as belonging to the process of segmentation. Later they were 
described by Marchiafava and Celli as vacuolated parasites, the highly refract- 
ive nuclear bodies appearing in the fresh condition very much like vacuoles. 
Still later, Celli and Guarnieri sketched them from specimens stained in the 
fresh condition, regarding some as showing partial segmentation, others as 
vacuolated parasites, although they accurately described the appearance of the 
nuclear particles invariably found within these " vacuoles," while others they 
supposed to be groups of confluent parasites, i. e., true plasmodia. Manna- 
berg's descriptions (1899), referring only to fresh blood, do not include 
these bodies, nor have they found a distinct place in his plates, although some 
of the figures in Plate IV. indicate that they have not escaped his observation. 
In Thayer and Hewetson's careful study of the parasite in fresh blood, the 
pre-segmenting bodies are not described as such. Laveran (1898, page 62) 
refers to the similarity in appearance between a nuclear body and " vacuole," 
but he neither describes nor depicts the pre-segmenting reticulated parasite. 
Ziemann describes the pre-segmenting bodies as they appear after his or 
Romanowsky's staining methods, but the plates would not enable one un- 
familiar with the subject to identify these forms in specimens stained by eosin 
and methylene blue. 

The reticulated, pre-segmenting, tertian parasites may be seen in 
every case examined within six to eight hours preceding the chill, 
and often in belated parasites shortly after the chill. Many transi- 
tional stages between the homogeneous adult parasite and the perfect 
rosette may be seen in rich infections. They are well demonstrated 
by eosin and methylene blue, especially as regards the increasing 
density of stain and reticulation. After hematoxylon the multiple 
nuclei stain deeply. 

By Nocht's method a series of interesting nuclear changes may be followed 
in the pre-segmenting forms. After the mass of enlarging chromatin granules 
and milky substance has flown out into the elongated form described above, 
the chromatin granules leave the central clear space and make their way in 
groups out into the body of the parasite. Various stages of this process may 
be followed in specimens taken at suitable periods, and some observed phases 



3IALABIA. 441 

are seen in Plate XIV., Figs. 13 to 15. Considerable differences in the num- 
ber of such groups may be noted in different cases. Usually a large number 
of ill-defined groups are seen before the central mass of granules is exhausted. 
(Plate XVI., Fig. 14.) In some specimens the compact nuclei of the young 
spores appear to form in one segment of the parasite before the main mass of 
granules has become exhausted. Each of the groups appears always to be sur- 
rounded by a milky zone, and the mass of granules is often of a peculiar tri- 
angular form. During these changes the pigment granules increase in size, 
diminish in number, and are distributed in the meshes of the now distinctly 
reticulated body of the parasite. 

In the late stages of infection rather small but full-grown forms may be 
found with four to six groups of chromatin granules. It seems probable that 
these bodies are destined to flagellate, and are developed from the compact, 
densely staining forms of younger parasites. 

7. Tertian rosettes are usually seen in the circulation three or four 
hours before the chill, most abundantly just before the chill, and a 
few are often to be found for one hour or longer after the chill. 

These limits may occasionally be much wider, as Marchiafava and 
Celli have seen rosettes two to six hours before the chill and six to 
seven hours thereafter, and, indeed, when the different broods of 
parasites are not very distinct, there is no reason why occasional 
rosettes should not be found at any period of the main cycle. 

Of the three types of sporulation described by Golgi, the second type, ac- 
cording to which the entire parasite is divided into spores, leaving nothing 
but pigment, is undoubtedly the usual process. As regards Golgi's first type, 
after which only the peripheral portion of the parasite divides, leaving a distinct 
central, globular, pigmented body, most stained specimens fail to show con- 
vincing evidence that the physiological segmenting process may be subject to 
such an important modification, nor does it appear in recent literature that the 
existence of this variety of segmentation has been fully verified. In a few 
cases taking quinine the writer has seen rare segmenting bodies which re- 
sembled those described as above by Golgi, but never in fresh' cases. Golgi's 
third type of " partial segmentation," together with the lateral circumscribed 
sporulation of Celli and Guarnieri, may frequently be seen in rich tertian in- 
fections in fresh blood, but, according to the evidence of stained specimens, 
must be classed with the pre-segmenting forms. The various morphological 
differences seen in the segmenting forms of the separate species serve to dis- 
tinguish those species, but do not constitute different types of this process. 

The tertian rosette is usually distinguished by its large size and 
considerable number of spores — fifteen to twenty. From the writer's 
specimens it does not appear, however, that the identification of the 
tertian rosette can always be based upon the number of spores, as 
these are sometimes found to number under fifteen, though rarely 
over twenty-one. Marchiafava and Bignami, however, have de- 
scribed tertian rosettes with forty to fifty spores. With the smaller 
number of spores the ro.sette is always distinctly larger than either 
the quartan or the estivo-autumnal body. 

Although rosettes sometimes appear to be extracellular when seen 
in fresh blood, in stained specimens the writer has n^ver seen a clearly 
extracellular segmenting tertian body. Almost invariably there is 
an unbroken ring of hemoglobin about the parasite, and very often 
traces of hemoglobin may be found scattered through a mass of 
spores, where they may be demonstrated by dense staining with 
eosiu. 



442 ANIMAL PARASITES. 

The nuelear changes demonstrated by Nocht's method in the tertian 
rosette consist principally in the gradual fusion of the new-formed 
groups of chromatin granules into one compact globule, which is partly 
surrounded by a '' milky zone/' which is probably an artifact. 

While the rosette is still compact the vesicular shape of the spore 
is distinct. The outer segment of the ring is usually thickened, the 
nucleus tends to lie near the inner pole, and between the nucleus and 
the outer segment is a small, milky zone. 

The pigment is usually collected into a central block or mass of 
granules, but may be found variously scattered among the spores, or 
along the periphery of the rosette. (Plate XIV., Fig. 17,) 

The Quartan Parasite. The earliest form of the quartan para- 
site as seen in the stained red cell is practically indistinguishable 
from that of the tertian organism, but its true character may usually 
be suspected from the slightly shrunken appearance of the infected 
cell. In fresh specimens the higher refractive quality of this body 
is often, however, sufficiently characteristic for its identification. 
After a very slight increase in size the quartan parasite becomes 
rather easy to distinguish in both fresh and stained specimens, for it 
early takes the form of a ring, of the general character of the tertian 
ring, but smaller, more compact, and more richly and coarsely pig- 
mented. As with the tertian organism the nuclear body is found 
projecting into the ring. In fresh specimens at this period the 
higher refractive quality and slower ameboid motion are additional 
diagnostic characters from the tertian parasite. (Plate XV.) 

The growth of the quartan ring is very similar in all important 
respects to that of the tertian, while its distinguishing features, espe- 
cially the abundance of coarse pigment grains, are uniformly retained. 

Daring the pre-segmenting stage the characters of the quartan 
parasite are markedly different from those of the tertian. On account 
of the slower progress of sporulation, and from the greater tendency 
of the quartan parasite to complete its cycle in the general circula- 
tion, quartan pre-segmenting bodies are relatively much more 
numerous in the stained specimen than are the similar forms of the 
tertian organism. In some specimens taken several hours before the 
chill the majority of organisms found may present the markedly 
reticulated structure indicative of approaching division. The multi- 
ple nuclei being less numerous and the pigment more abundant, the 
meshes of the reticulum are much coarser and the pigment is often 
found in irregular, partly radiating rows. These coarsely reticulated, 
relatively small, and richly pigmented bodies, lying in markedly 
shrunken cells, are very characteristic and not readily confused with 
any other form of malarial parasite commonly found in the peripheral 
blood. In some severe estivo-autumnal infections, showing many 
parasites of all stages in the peripheral blood, somewhat similar sphe- 
roidal or pre-segmenting forms may be found in considerable num- 
bers, but, as will be seen by reference to Plate XVI., the character 
of the pigment in the estivo-autumnal parasite is very different, 
while such cases are very rare, and readily recognized on clinical 
grounds, being almost invariably of the pernicious type. 



PLATE XV 




Cycle of Quartan Parasite. 



Fig. 1. Very early non-pigmented form. 

Figs. 2, 3, 4. Small quartan rings, with large chromatin masses and abundance of pigment. 



Turban-shaped ring, with subdi^dded chromatin. 

Subdi^dsion of ring and of chromatin granules. 

Coarse quartan ring with central chromatin granules. 

Full-grown quartan jDarasite, with eccentric chromatin, hyaline body, and abundance 
of pigment. 

Extra-cellular reticulated body. 
Figs. 10-13. Quartan presegmenting forms. 
Fig. 14. Quartan rosette. 
Fig. 15. Pigmented mononuclear leucocyte. 



Fig. 5. 
Fig. 6. 
Fig. 7. 

Fig. 8. 

Fig. 9. 



MALARIA. 443 

The quartan segmentiag bodies are usually more abundant in the 
peripheral circulation than are rosettes of any other type, and are 
readily identified by the small number (six to twelve) and compara- 
tively large size and geometrical arrangement of the spores. (Plate 
XY.) 

The Estivo-autumnal Parasite. The following description 
applies to a group of organisms, which, according to the Italian 
school, comprises two or three varieties of malarial parasites. Waiv- 
ing for the present the question of a plurality of species, the entire 
group will be described as one, and the grounds for their separation 
into two or more species will be considered later. 

The earliest form of the estivo-autumnal parasite seen in the red 
cells is very similar to that of the tertian and quartan parasites, but 
is of slightly smaller size than eitner, and is often distinguishable 
from the tertian by the shrinkage of the cell, and from the quartan 
by its distinctly smaller dimensions. (Plate XVI., Fig. 1.) In 
fresh specimens the young ameboid body usually shows a low refrac- 
tive index as compared with the tertian and quartan parasites. It 
is never pigmented. Associated with the intracellular spores there 
are frequently seen in the plasma small spheroidal bodies exhibiting 
an active rolling motion and occasional blunt projecting points (pseu- 
dopodia?), and which, on becoming arrested by contact with the red 
cells, are found to be indistinguishable from compact intracellular 
bodies. The positive identification of these extracellular bodies, how- 
ever, appears to the writer a very hazardous undertaking (cf. 
Ziemann, p. 49). In dried specimens stained by Nocht's method, 
however, the young extracellular parasite may be positively identi- 
fied from the presence of a mass of chromatin. In the writer's 
specimens such extracellular bodies were very rarely encountered. 

The Estivo-autumnal Signet-ring. At a very early period of its 
development the estivo-autumnal parasite assumes a very character- 
istic ring shape. Many of these rings early develop a thickening of 
one segmeut, and to these bodies of various sizes the term ^' signet- 
ring '^ very aptly applies. (Plate XVI. , Figs. 5 to 7.) 

It is to be noted that in some cases the rings fail to exhibit this 
thickening but remain of a uniform hut very fine calibre throughout, 
(Plate XVI., Fig. 4.) The period during which the rings retain 
this uniform calibre has not been determined, but bodies of this type 
may be seen measuring at least 3// in diameter. They nearly always 
present two nuclear bodies, lying at opposite poles or close together. 
Occasionally such lungs are found to have unfolded, and to be 
stretched like a thread clear across the cell, the nuclei appearing at 
inconstant intervals. 

In other cases no rings of this type are seen, all showing the 
thickening of the signet and a single nuclear body. In the majority 
of cases rings of both types are associated in variable numbers. 

Multiple infection with the young rings is very common in the red 
cells of most cases of estivo-autumnal malaria, and, as a rule, its 
frequency is proportionate to the severitv of the disease. In the 
peripheral blood three parasites are often found in the same red cell. 



444 ANIMAL PARASITES. 

and occasionally four, while in smears of the marrow of a fatal case, 
seen by the writer, infection of one cell with four rings was common, 
five parasites were occasionally seen in the same cell, and one slightly 
swollen red cell was encountered containing seven well-formed rings. 
These observations accord with the reports of Ziemann, who found 
often three and four parasites, and once as many as five in one 
cell. 

It appears in the description of the hemameba immaculata, which is said to 
sporulate without producing pigment, that most of the rosettes contain com- 
paratively few spores, averaging from six to ten (Marchiafava, Bignami, 
Ziemann, Marchoux, Grassi and Feletti). The close resemblance to a non- 
pigmented rosette presented by some of these red cells harboring five, six, or 
seven young parasites is very striking. In the writer's specimens (see Plate 
XVI., Fig. 2) there could be no doubt as to the proper interpretation to be 
placed on these examples of multiple infection. 

Multiple infection of the red cell appears in rather rare instances 
to lead to the development of a peculiar form of the young estivo- 
autumnal parasite on which Mannaberg bases his unique theory of 
the development of crescents. This body consists in the apparent 
union of two rings by a f asion of their nuclear bodies. (See Plate 
XVI., Fig. 3.) Mannaberg depicts all transition forms between 
these bodies and the fully developed crescents. 

The signet-ring forms frequently reach a diameter of 4// while 
still retaining the peculiar thickening of one segment, the thin 
geometrical bow, and a very distinct nuclear body staining with 
methylene blue and surrounded by a narrow achromatic zone. (Plate 
XYL, Fig. 6.) 

Beyond this size, when persisting in the finger blood, the growth 
of the parasite produces an irregular body in which the outline of the 
ring becomes more or less obscure. The full development of the 
large signet-rings appears to require about twenty-four hours. 

In the majority of cases the ring forms seen in the peripheral blood 
fail to show any trace of pigment, especially in the patients showing 
distinctly intermittent quotidian or tertian paroxysms. In a con- 
siderable number of instances, however, especially in very severe 
and fatal infections, the largest rings exhibit a very few minute pig- 
ment grains, usually associated with older pigmented forms. 

The distinguishing features between the estivo-autumnal and the 
tertian rings have been enumerated under the description of the latter 
parasite. 

Later Stages of the Estivo-autumnal Parasite. The later forms of 
the estivo-autumnal parasite are rather rarely seen in the peripheral 
circulation. 

Most of the Italian writers speak of their occurrence in the finger blood as 
being very unusual, but not unknown, Saccharoff in two cases of estivo- 
autumnal infection saw many rosettes in the peripheral blood. Ziemann 
reports that in malignant tertian cases occurring in Italy he could follow in 
the blood the complete cycle, but that in cases occurring in Kamerun the later 
forms were not found in the finger blood. Plehn describes a variety of para- 
site which he believes is peculiar to hemoglobinuric fever, and of which the 
later forms are of very small size, but abundantly represented in the peripheral 



PLATE XVI 





•••• 






u 






^^ ^^." 



20 



-O.**.'* 

1%^ 







Cycles of Estivo-Autunmal Parasite. 



Fig. 

Fig. 

Fig. 

Fig. 

Fig. 

Figs. 

Figs. 



Very young form. 

Infection of one cell with seven young jDarasites. (Drawn from a marrow smear.) 

Triple infection. Two parasites joined b^- single chromatin mass. 

Double infection. Peculiar rings with two chromatin grains at opposite poles. 

Double infection. Small ring adherent to cell. 
7. Signet-ring forms. Subdivision of chromatin. 
9. Later ring forms, with subdi^'ided chromatin and few pigment grains. 



Figs. 10-12. 



Figs. 

Fig. 

Fig. 

Figs. 

Fig. 

Figs. 

Fig. 

Fig. 24 



Fig. 
Fig. 



Full-grown forms with finely subdi^dded chromatin and gradual concentration of 
pigment . 
13, 14. Stages of presegmenting forms, with concentrated eccentric pigment. 

15. Doiible infection with separate presegmenting bodies. 

16. Estivo-autumnal rosette. 
17, 18. Young crescent and ovoid. 

19. "Pulsating" crescent. 
20-22. Various forms of crescents. 
23. Two bows about single crescent. 

Fully developed crescent; two masses of chromatin ; acliromatie •substance: double 
wreatlis of pigment. 

25. Diagrammatic flagellating body. 

26. Extra-cellular sterile bodv. 



MALARIA. 445 

blood. In five cases examined by the writer the entire developmental cycle of 
the estivo-autumnal parasite could be followed in the peripheral blood, and on 
the forms observed in these cases is based the present description of the later 
phases of this parasite. 

After the ring has reached its fall size {4fjL, twenty-four hours +) 
the swollen segment begins to increase in bulk and to involve a 
larger portion of the circumference^ yielding forms seen in Plate 
XVI., Figs. 8 and 9. Some of these forms closely resemble the 
turban-shaped rings of the tertian parasite (Plate XIII., Fig. 8), 
but are much smaller. A few fine pigment grains were usually 
found scattered along the periphery of the growing segment. Forms 
corresponding to the full-grown tertian parasite with homogeneous 
body are rarely seen in the peripheral blood. When encountered 
they are found to occupy three-fourths of the shrunken cell, stain 
homogeneously with methylene blue, and fail to exhibit a distinct 
nuclear body after methylene blue or hematoxylon. 

Most of the larger forms of the parasite seen in the peripheral 
blood give evidence of approaching segmentation, exhibiting a dis- 
tinctly reticular structure and a condensation of pigment into one 
or two clumps. (Plate XVI., Fig. 10.) In many of these bodies 
the original ring persists at one segment of the parasite, but appears 
to be of reduced size, and is sometimes subdivided by strands of 
protoplasm. The nuclear body at this period fails entirely to stain 
with methylene blue and is indistinct after hematoxylon^ resembling 
in this respect the full-grown, homogeneous, tertian organism. The 
presence of a distinct achromatic spot adjoining the clump of pig- 
ment is very frequent in these forms, and this spot is found by 
Nocht's stain to be composed of chromatin granules. 

The further development of the pre-segmenting forms is repre- 
sented in Plate XVI., Figs. 11 to 15, two separate parasites in the 
same red cell being occasionally seen. In them the reticular structure 
becomes more distinct, the pigment is still further concentrated, and 
the subdivided nuclear bodies appear as small achromatic spots in 
the meshes of the reticulum and again stain distinctly with hema- 
toxylon. 

Estivo-autumnal rosettes appear in the peripheral blood of rare cases 
only and in moderate numbers, and exhibit a very uniform structure. 

The pigment is grouped in a central granular clump, or, rarely, 
somewhat scattered. The spores seem to be arranged in two rows, 
but this appearance is probably an optical effect produced by the 
flattening of the more or less spheroidal body of the rosette, the 
spores originally lying in the central axis of the rosette falling, in 
the hardening process, within those lying on the periphery. 

When admitting of accurate enumeration their numbers are found 
to vary between eighteen and twenty-one. The same number of 
spores was repeatedly counted in favorable specimens, made by the 
writer from the marrow of a fatal case. In sections of the tissues 
of fatal cases, however, the number of spores appears to vary between 
wider limits, i. e., eight to twenty, but as the entire rosette need not 
always be included in the section the observations made in smears 



446 ANIMAL PARASITES. 

are the more reliable. A rim of hemoglobin invariably surrounds 
the rosette, and strands of hemoglobin are frequently found running 
between the spores for a variable distance, sometimes within the 
outer row. 

These rosettes differ from the tertian segmenting forms in the smaller 
size of the body and shrunken appearance of the cell., and in the small 
size, but not in the number , of the spores. 

The Changes in the Chromatin of the Estivo- autumnal Parasite.— In the 

young ring forms the early subdivision of the chromatin has been noted by 
Gautier, and in the writer's specimens was a prominent differential character 
from the tertain rings. A great variety of appearances is produced by the 
irregular subdivision and distribution of the chromatin in the young estivo- 
autumnal parasite, many of which have been sketched or described for the ter- 
tian rings. The grains are usually quite small and are sometimes apparently 
fused into a spindle-shaped mass, lying within the ring. Other peculiarities 
which may be noted are : a markedly unequal size of the grains, a widely sep- 
arate position, a frequent concentration in the centre of the ring, and, very 
rarely, a complete absence of chromatin. 

After twenty-four hours' growth the chromatin granules become more numer- 
ous and extremely minute, and are inclosed in a trace of the milky substance, 
as in the tertian parasite. 

The changes in the chromatin in the pre-segmenting estivo-autumnal body 
are similar to those of the tertian parasite. In some of the writer's specimens 
the chromatin granules were found in radiating lines stretching from the 
parent mass to the new peripheral groups. In many specimens the peripheral 
groups of granules were well formed, while the central portions of the body 
contained many diffuse granules. The relative quantity of chromatin in some 
of these bodies appears surprisingly large. The spores in the mature rosette 
usually contain single compact grains of chromatin, which stain readily by 
methylene blue, but in some rosettes two large granules of chromatin are seen 
in a few spores, although the rosette seems ready to burst. 

The double nuclei seen in many young estivo-autumnal rings may, perhaps, 
be referred to the incomplete fusion of the chromatin in the rosette. 

Characters of the Pigment of Estivo-autumnal Parasites. When 
any considerable quantity of pigment gathers in the estivo-autumnal 
parasite it is usually found in one or two groups, but rarely is 
diffuse. 

When the parasite has reached the full-grown, homogeneous stage 
the pigment is commonly found concentrated in a single compact 
mass. This early concentration of pigment is one of the chief 
features which distinguish the estivo-autumnal from the tertian 
parasite in the pre-segmenting stage. This fact has been fully 
emphasized by Gautier, and was very uniformly illustrated in the 
writer's cases. 

The Plurality of Species in the Estivo-autumnal Group of Parasites. 
The probability that several species of parasites are concerned in the 
severe types of malarial fever prevailing in tropical countries, espe- 
cially in the summer and autumn, has been chiefly maintained by 
the Italian school, who divide this group of parasites into two 
species: (1) the quotidian, and (2) the malignant tertian. 

1. The Quotidian Parasite. The typical fever curve of this variety 
is rather rarely seen, more frequently in relapses than in initial seiz- 
ures, while a postponement of paroxysms is usually observed, and a 
continuous fever is very common. The typical attack is short, the 



31 A LABIA. 447 

fever lasting six to eight, rarely twelve hours, the temperature then 
falling to 37° C. 

The descriptions of the morphology of this parasite unfortunately 
refer only to its appearance in fresh blood. During the rise of the 
temperature, the sweating stage, and the first hours of apyrexia, the 
blood is found to contain a variable number of red cells infected 
with one or more very actively motile or non-motile parasites of 
discoidal or ring shape. During the afebrile period the parasites 
increase in size, the ameboid motion diminishes or ceases, and fine 
pigment grains are deposited along the periphery of the organism. 
Later, in the larger forms, the pigment gathers in a single clump or 
heap of grains. Daring the entire development the infected red cell 
diminishes in size and presents a '^ brassy^' color as a result of 
'^ acute necrosis'' induced by the parasite. Rosettes are seldom 
encountered in the finger blood, segmentation occurring principally 
in the internal organs, as seen in the aspirated splenic blood. Rarely 
segmentation occurs before pigmentation, but usually the numerous 
round or oval spores are found grouped about a central pigment 
mass, the rosettes being much smaller than those of the quartan or 
mild tertian parasites. 

Contrary to the rule in malignant tertian infections, the young 
parasites are found in the blood from the beginning of the paroxysms, 
and, except in very mild cases, there is no period in the cycle when 
the parasites are absent from the finger blood. 

2. The malignant tertian parasite is distinguished on both clinical 
and morphological grounds. Clinically the typical paroxysm begins 
with a sharp elevation to about 40° C, tlie febrile period lasts 
twenty-four or thirty-six to forty hours, is marked by b, pseudocrisis 
and precritical elevation, the fever describing in the three-hourly 
chart a very characteristic course which differs from that of the mild 
tertian paroxysms. A tendency toward various irregularities is 
common. 

In the blood the parasites may be scarce or even entirely absent at 
the beginning of the paroxysm. At the height of the fever the red 
cells contain small, non-motile, ring, or disk-shaped bodies, or irregu- 
lar, ameboid bodies, which begin to show pigmentation toward the 
approach of the afebrile period. Most of the parasites then dis- 
appear from the finger blood, and rosettes are rarely seen except in 
some very rich infections. The pre-segmenting forms are round or 
ovoid, one-fourth to one-half the size of the red cell, and the pigment 
is gathered in a single clump or in a mass of vibrating granules. 
The rosettes occupy about two-thirds of the red cell, and exhibit two 
rows of spores which usually number ten to twelve, rarely fifteen to 
sixteen. The infected cells are markedly shrunken and present a 
^^ brassy or golden" appearance. 

The authors distinguish the malignant tertian parasite from the 
commoner or mild variety on the following features : 

1. The malignant tertian parasite is smaller in all stages. 2. Its 
pigment is less abundant and often non-motile, while in the other the 
pigment is very abundant and always in vibratory motion. 3. The 



448 ANIMAL PARASITES. 

rosettes are smaller, contain only ten to twelve (rarely sixteen) spores, 
and are rarely seen in the finger blood. 4. The infected cell is 
shrunken instead of being swollen, as with the mild tertian infection. 
From the quotidian parasite the malignant tertian is distinguished 
on the following grounds : 

1. The tertian ameba is, in corresponding stages, larger and less 
transparent than the quotidian. 

2. In the malignant tertian parasite the ameboid movement is 
livelier, so that the resting discoidal forms are less frequent than 
with the quotidian parasite. The larger, pigmented, tertian forms 
also are often ameboid, this property persisting for twenty-four 
hours or longer. 

3. The pigment in the tertian parasite is often vibratory, but 
never in the quotidian. 

4. In the quotidian rosettes pigment is sometimes wanting. 

5. The appearance in the finger blood of a new generation of 
tertian parasites is seen some hours after the beginning of the 
paroxysm, therefore much later than with the quotidian infection. 

Marchiafava and Bigaami admit that the similarity between the malignant 
tertian and the quotidian parasites is very great, and that the differential diag- 
nosis is difficult, and possible only from the full-grown forms seen just before 
the paroxysm. They apparently do not feel quite certain that the quotidian 
and malignant tertian parasites are separate species, as is indicated by the 
following extract from their discussion on this point {Sydenham Society 
Transactions^ P- 8) : 

" The remarkable points of resemblance between the quotidian and malig- 
nant tertian parasites make it very difficult to solve the question whether we 
have to do with different sorts of parasites in the strict sense, or with one and 
the same parasite which varies greatly in the time of its development — twenty- 
four to forty-eight hours — and there are all intermediate degrees. On this 
latter theory it becomes easy to ascribe the morphological differences to the 
varying length of the cycle. Bat various facts oppose this hypothesis. First, 
the clinical types of the quotidian and tertian are clearly distinct from each 
other, and have a certain stability which is maintained in relapses and recur- 
rences. Second, we have never met with intermediate forms or transitional 
cases, although it is very difficult to interpret the irregular fevers. Grant- 
ing that the question cannot, at present, be solved definitely, ... we 
are inclined to adopt the view that the ameba of the quotidian and the 
ameba of the summer tertian are closely related varieties of one and the same 
parasite." 

This view is not materially altered in the authors' last treatise (1900). 

Mannaberg and Grassi and Feletti accept the views of Marchiafava 
and Bignami and describe a quotidian parasite, but do not furnish 
original observations tending to confirm their opinions. Thayer and 
Hewetson, Ziemann, and Gautier, all of whom have studied very 
minutely the estiv^o-autumnal parasites, the latter authors from 
extremely rich material in tropical regions, fail to find sufficient 
grounds for the subdivision of the group. 

From the writer's study of cases at Montauk among soldiers 
arriving from Cuba in 1898, it was concluded that it is im- 
possible from the observation of parasites in the peripheral blood 
to demonstrate the existence of a twenty-four-hour cycle, since the 
infecting broods are seldom compact. Quotidian paroxysms always 



MALAEIA. 449 

seemed to be referable to iDfection with two broods of malignant 
tertian ameb^e. 

Two features were noted, however, which offered some hope of 
distinguishing a quotidian from the tertian parasite : 

1. The exclusive presence in a few instances of rings with double 
nuclei and without the signet. 

2. The appearance of large numbers of very small adult parasites 
in the peripheral blood. 

Neither of these features proved sufficient for the positive identifi- 
cation of a quotidian parasite. The peculiar rings were usually 
associated with the ordinary signet-ring forms, and the rosettes seen 
in peripheral blood were identical in appearance with those found in 
marrow-smears from fatal cases of malignant tertian infection. 

It, therefore, seems necessary to conclude for the present that a 
special quotidian parasite has not yet been demonstrated and probably 
does not exist. As stated by Ziemann, it seems likely that estivo- 
autumnal fever is caused by a single species of parasite whose devel- 
opmental cycle usually requires forty-eight hours, but may possibly 
be completed in twenty-four, or, as in one of his cases, may be pro- 
longed to seventy-two hours. 

The Hemameba Immaculata. Grassi and Feletti, Marchiafava, 
Celli and Bignami, Guarnieri, Saccharoff, Marchoux, and Ziemann 
report cases in which rosettes were found in the blood or viscera 
which were free from pigment. Most of these authors, while 
admitting that the parasites may occasionally sporulate without pro- 
ducing pigment, are not inclined to regard the hemameba immaculata 
as a separate species. Grassi and Feletti claim to have observed in 
a bird exclusive infection with a variety of parasite which fails to 
produce pigment, and regard the appearance in the human subject 
of rosettes without pigment as evidence of infection by a distinct 
variety of parasite. Mannaberg also accepts this classification. 

In the report of the examination of the viscera of this bird no mention is 
made of the presence or absence of pigment, and it is impossible to determine 
whether or not the infection had failed to produce pigment in the viscera as 
well as in the peripheral blood. 

In all cases in which pigment-free rosettes have been found in the 
blood of human subjects there have been found the usual pigment 
deposits and pigmented rosettes in the viscera. That there is con- 
siderable variation in the quantity of pigment produced by the 
parasite in fatal cases is shown by the reports by Marchiafava and 
Bignami of fatal cases in which a microscopic examination was 
required to show the presence of very scanty deposits in the viscera. 

Ziemann mentions that he has seen a pre-segmenting body of the 
benign tertian type which was entirely free from pigment. 

The writer believes that some examples of multiple infection of 
red cells have been mistaken for pigment-free rosettes, but this 
explanation can hardly apply to the reports of many such rosettes 
in the cerebral capillaries. The majority of observers, including 
Marchiafava and Bignami, believe that there is no pigment-free 

29 



450 ANIMAL PARASITES. 

variety of human malarial organism, but that the estivo-autumnal 
parasites may occasionally fail to elaborate pigment. 

The Crescentic Bodies. On the fourth to sixth days of any but 
initial paroxysms of estivo-autumnal infection the peripheral blood 
may contain red cells infected by spheroidal, oval, elliptical, or small 
crescentic bodies which represent the early forms of the sexual cycle 
of the parasite. The relation of these forms to the young ameba is 
not clear, and it is not known whether the crescents develop directly 
from the spores or from some parent body, such as is seen with 
various coccidia, and in which the young parasites are of creseentiG 
form before their discharge from the mother cell. The latter view is 
the more probably correct, being favored by analogy, but the earliest 
forms of crescents are very frequently spheroidal or elliptical. On 
the other hand, neither direct observation nor analogy favor the 
view that they spring directly from the ordinary ameboid parasites 
of the pyrogenous cycle, as claimed by Marchiafava, Celli, and 
Bignami. 

Maurer describes the development of crescents (gametes), both from the dif- 
ferentiation of the small, ring-shaped, ameboid parasite, and from the merozo- 
ites of sporulating crescents. He identifies the early developing crescent on 
the following features : It first exhibits a ring form, but of coarse calibre, with 
one or two chromatin granules lying in the protoplasm of the parasite. It 
soon enters the red cell, where it loses the ring form and becomes compact, 
whereas the ameboid ring long remains on the outside of the cell. Within the 
cell it soon develops considerable pigment, absorbing the Hb and contracting 
and condensing the body of the cell without the formation of the striking 
changes in the cell described by Schuffner as tiipfelimg (stippling). This break- 
ing up of the cytoplasm of the red cell into coarse granules Maurer claims to 
be present only in cells infected by the ameboid parasite. In its further 
growth the gamete becomes enlarged, spheroidal, then kidney-shaped or 
crescentic. 

Mannaberg regards the crescents as the syzygia developing from the union 
of two young parasites, and, while this view is lacking in support from the 
actual demonstration of two parasites uniting to form the crescent, and is 
entirely contrary to the recognized mode of origin of homologous forms in 
other protozoa, there are some morphological features which are somewhat in 
its favor. These are the appearance, frequently, of two groups of pigment, 
occasionally of two masses of chromatin, and the isolated observation of two 
halters with one crescent. 

Appearing first as bodies somewhat shorter than the diameter of 
the red cell, through various changes in length, breadth, and shape 
(see Plate XVI.), the adult crescent is developed, appearing in the 
blood usually after the fifth to the seventh days of the paroxysm. 
The average adult crescent measures about 9// to 12/>( in length, by 
2[i to 3/i in breadth, but in some cases very large or giant crescents 
have been observed, the writer having seen specimens measuring 
20// by 5//. While the young crescent contracts and swells, altering 
its shape, the older forms are quiescent, and neither show true 
ameboid properties. The ends are either pointed or blunt, many 
old specimens appearing with swollen ends. 

Thepi^me?!^ is in the form of coarse, golden-yellowish grains, rods, 
or possibly at times in rod-shaped crystals. It is the coarsest pig- 
ment elaborated by the parasite, and is always more abundant than 



MALARIA, 451 

in the ameboid bodies of equal size. It is arranged in a single cen- 
tral mass or circle, or as a double circle resembling a figure 8. 
Occasionally it is found in scattered groups, especially in very large 
crescents. 

Although a membrane cannot be said to exist about the crescent, 
yet its outer border may be stained reddish by eosin, and it has, 
therefore, been supposed that a remnant of Hb surrounds the crescent 
on all sides. The membrane or thickened outer border of the red 
cell is closely applied about the convex side of the crescent, while 
across the concavity it stretches loosely like a halter. The writer 
has seen two of these halters spanning equal segments of the con- 
cavity of a single large crescent (Plate XVI., Fig. 23), while Mar- 
chiafava and Bignami have seen two adult crescents within a single cell. 

In the centre of the crescent is a sharply marked, light-blue stain- 
ing, or achromatic area of variable size, containing the chromatin 
and usually also the pigment. Marchiafava and Bignami describe 
the nucleus of the crescent as vesicular, but for reasons already stated 
the writer is unable to regard the nucleus as consisting of any other 
structure than the mass of chromatin granules, which can always be 
found in living crescents. In the young crescent these chromatin 
granules are of larger size than in the adult body, in which they 
become subdivided, and, when obscured by pigment, extremely 
difficult to detect. Sometimes there are two separate groups of chro- 
matin granules. Marchiafava and Bignami expose most specimens 
containing crescents in a moist chamber for a few minutes, thereby 
causing the pigment to separate, the nucleus to swell, and the chro- 
matin granules to be more apparent. With Nocht's method this 
expedient is seldom necessary. 

Maurer describes certain features which he claims may distinguish 
the male (microgamete) from the female crescent (macrogamete). 
The male is short, thick, and kidney-shaped, or swollen at one end, 
densely staining, and its pigment is more often scattered. (Plate 
XVI., Figs. 17 to 23.) The female is more elongated, less densely 
staining, and exhibiting more compact pigment grouped about two 
or three centres. 

Although crescents may show transverse segmentation and occa- 
sionally lateral budding, these changes are probably degenerative, 
as is also their vacuolation. Former views regarding their multipli- 
cation by various methods are now known to be erroneous. Maurer's 
recent description of sporulating crescents is quite unsatisfactory. 

That the marrow is a special seat of the development of crescentic 
bodies is believed by Councilman, Bignami, and Bastianelli, who 
have found an excessive number of young forms in this tissue when 
they were scarce elsewhere. 

The long persistence of crescents in the blood and their resistance 
to quinine are matters of common clinical observation. Yet Leuko- 
wicz, who describes several varieties of crescents, denies that they 
are any more refractory to quinine than are the ameboid forms. 

Flagellate Bodies. When blood containing crescents is allowed 
to stand in the air or under a cover-glass for a few moments some of 



452 ANI3IAL PARASITES. 

the crescents slowly assume the spheroidal form, active vibratory 
oscillations of the pigment granules begin, and soon, from one or 
more points, pseudopodia shoot out with active lashing movements. 
These flagella continue their movements for some time, changing 
their position actively, their shape slowly, while some may be seen 
to break off from the body and swim off through the plasma. The 
formation of flagellate bodies represents the second stage in the sexual 
C3^cle, probably never occurring in the human body. 

These flagellate bodies are found, on staining, to be composed of a 
spheroidal, pigmented mass, usually surrounded by a remnant of the 
red cell, of two to four flagella of variable type, of one or more lateral 
buds, and of chromatin, which has now undergone a remarkable 
transformation. The bulk of chromatin is apparently much increased, 
and most of it is usually found in the form of long, slender threads 
within the flagella. Occasionally short threads of chromatin may be 
found within the sphere. The flagella are composed of an outer 
protoplasmic covering, their ends are blunt or pointed, their borders 
even or bulbous, and while most of them contain chromatin threads 
some are entirely lacking in this constituent. 

Not all crescents develop flagella. Some remain in the semilunar 
form, exhibit slow, undulatory movements, and tend to stain more 
deeply with methylene blue. It is believed that these crescents are 
penetrated by a motile flagellum, after which they become actively 
locomobile, and it is further supposed that these motile fertilized 
crescents or ^' vermicuU '^ are capable of penetrating the wall of the 
mosquito's stomach, and there developing the encysted bodies, which 
are the next stage of the bisexual growth of the parasite. 

The evidence on which this relation of two varieties of crescents is indicated 
is largely derived from analogous phenomena, known to occur among various 
coccidia, Simond and Siedlecki, in the coccidia, have seen the fertilization ot 
one crescentic body by the motile flagellum of another, and MacCallum, ex- 
amining the parasites of crows, has seen the entrance of a flagellum into a 
crescent with the development of a motile vermiculus. (See Solley and 
Carter.) The same evidence indicates that the flagella are motile chromosomes 
of a karyokinetic nucleus, and that their function is that of a male fertilizing 
element. It thus appears that the crescents and their flagellated derivatives 
constitute a developmental series destined to perpetuate the species in the 
body of the mosquito. 

Tertian flagellate bodies develop from the full-grown tertian parasites 
of long-established infections in much the same way as from cres- 
cents. Of full-grown tertian parasites three varieties must be sepa- 
rated : (1) bodies which are destined to segment, and which the 
writer believes are often produced by conjugation ; (2) large hyaline 
forms which develop flagella ; (3) large hyaline forms with little 
chromatin which become fertilized by detached flagella. This last 
form has often been described in shed blood, and the writer has 
observed its fertilization in stained specimens of flagellate bodies. 

In the tertian parasite which is developing flagella, the chromatin 
increases in quantity, becomes arranged in a basket network, breaks 
up into several coarse filaments which may be found protruding 



PLATE XVII, 



Fig. 1. 



Ficr. 2. 




Fig. 3. 




Flagellating Malarial Parasites. 
Cerebral Cortex in Pernicious Malaria. 



Fig. 1. Tertian flagellate body. 

Fig. 2. Tertian flagellate body plunged into a red cell containing a macrogamete. 

Fig. 3. E.stivo-autuninal parasites in cerebral capillaries. 

Photographs by Dr. B. H. Buxton, from specimens prepared by the author and stained 

by Nocht's method. 



3IALABIA. 453 

from the edge of the sphere, and, finally, these filaments are discharged 
in the form of flagella, of which there are usually six to each parasite. 
Quartan parasites develop flagellate bodies very similar in appear- 
ance to those of the estivo-autumnal type. 

III. THE DEVELOPMENT OF THE MALARIAL PARASITE IN 

THE MOSQUITO. 

It is principally owing to the labors of Ross, at Hanson's suggestion, that the 
life cycle of the parasite in the mosquito has been elucidated. Ross followed 
the development of the prof eosoma of Labbe in the tissues of mosquitoes which 
had fed upon the blood of birds containing this malarial parasite. He traced 
the development of an encysted body in the wall of the intestine, and the 
formation therein of large numbers of so-called germinal rods. Finally, when 
the germinal rods were found abundantly in the salivary glands, the complete 
cycle of the parasite in the mosquito, and its natural mode of access to the 
human body were made clear. The demonstration was rendered doubly positive 
when Bignami succeeded in transferring the estivo-autumnal infection from 
one human being to another by passing it through Anopheles claviger, a species 
of mosquito found in the Roman Campagna. Later, tertian infection was 
transferred in the same manner. 

The details of the development in the mosquito have been worked 
out principally by Grassi, Bignami, and Bastianelli, while much valua- 
ble information regarding the few dangerous varieties of mosquitoes, 
their habits, and the means of identifying and destroying them have 
been contributed by Ross, Nuttall, the Italian writers, and by the 
Jenner School of Tropical Medicine. 

Developmental Forms. Two days after the mosquito has fed 
upon blood containing crescents there are to be found in the intes- 
tinal submucosa spindle-shaped, oval, or spheroidal bodies, resem- 
bling the spindle-shaped bodies of the blood. They contain a single 
nucleus, scattered pigment, and their protoplasm appears vacuolated. 
The actual development of these bodies from the crescents and the 
penetration of fertilized crescents into the intestinal wall have not 
been demonstrated. 

By the third to fourth days the bodies are much enlarged, dis- 
tinctly encapsulated, their protoplasm is reticulated, and their pig- 
ment has largely disappeared. 

By the fifth to the sixth days the encysted bodies have greatly 
increased in size, measuring up to 70fjt in diameter, and project into 
the celomic cavity. They are now found to contain numerous nuclei 
and globules resembling fat. 

By the seventh day fully formed germinal rods are found in the 
cyst in enormous numbers. These rods average about 14/j. in length, 
their ends are pointed, and at the centre of each is a granule of chro- 
matin. They are arranged in radiating or undulating masses about 
numerous centres. 

After the seventh day broken capsules are found which have dis- 
charged their rods into the celom, from which region they make 
their way into the salivary glands. 

In addition to encysted bodies which develop rods, some contain 
" brownish bodies ^^ of various sizes, the nature of which is not known. 



454 ANIMAL PARASITES. 

Very similar phases have been described for the development of 
the tertian parasite, while Bignami and Bastianelli have recently 
succeeded in tracing the similar phases of the quartan parasite. 

IV. CONJUGATION OF MALARIAL PARASITES. 

In 1897 the writer's attention was attracted by a specimen of 
blood from a rich tertian infection in which there were very numerous 
twin parasites of a younger broody while all the older parasites were 
single. A remarkable specimen of this type was secured at Montauk 
(in 1898) in which both broods were very compact and very numerous, 
and nearly all the younger parasites were twinned, while all the older 
forms were single. Extreme length and variety of ameboid processes 
also characterized the younger parasites in both specimens. Later 
the writer^ was able to follow such a case through one complete cycle, 
and found that the young twins were succeeded by full-grown single 
parasites of larger size. Finally, the application of Nocht's stain 
furnished convincing pictures of all stages of union, first of the 
bodies, later of the nuclei of the twin parasites, and left no room for 
doubt that under some conditions malarial parasites undergo a form 
of conjugation. 

The phases of this process are sketched in Plate XVIII. 

Usually the members of the conjugating pair presented distinct 
differences in appearance. One was a thick, compact parasite with 
abundant cytoplasm, one large and sometimes one smaller granule of 
chromatin, and was seldom seen in the ring form. The other was 
a ring-shaped parasite of delicate contour, of larger diameter, and 
with rather less chromatin. 

The separate development of each of these parasites was followed 
in these cases up to the large, spheroidal bodies. The compact para- 
site usually retained its compact form throughout, producing a 
parasite resembling in size the quartan forms, and staining very 
densely with methylene blue. In some instances it developed six 
or eight separate masses of chromatin granules, but the writer could 
not be certain that it sporulated. The delicate rings, developing 
singly, produced medium-sized, pale-staining parasites of full-grown 
appearance, but beyond this stage it was not followed. The conju- 
gating parasites produced large segmenting forms with sixteen to 
twenty spores. 

The extent and significance of this form of conjugation it is diffi- 
cult to determine. In the cases in which it can be profitably studied, 
parasites are usually very abundant, and in most cases few indica- 
tions of the process can be detected. It is, therefore, probably not 
essential to sporulation, and when parasites are scanty the chances of 
finding tvpical examples of conjugating pairs are greatly reduced, 
but the peripheral blood may not be a complete index of the processes 
in the internal viscera. The large size of the sporulating forms 
developed from conjugating pairs suggests that this process is intended 
to especially favor the multiplication of the species in the human 
host. It seems probable that conjugation occurs in the first genera- 



PLATE XVIII. 




Conjugating Cycle of Tertian Malarial Parasite. 



Fig. 
Fig. 
Fig. 
Figs 
Fig. 
Fig. 
Fig. 
Figs 

Fig. 
Figs 



1. Single compact body with double chromatin masses. 

2. Conjugating rings of xinequal size. 

3. Double infection with a coarse ring, double chromatin granules, and a tliin ring form. 

4. 5. Earh^ stages of conjugation of a thin ring and a compact body. 

6. Early ameboid figures of conjugating rings. 

7. Double nuclei in ameboid parasite. 

8. Union of nuclei, and subsidence of ameboid motion in older conjugating parasites. 

9, 10. Stages of union of bodies and of three chromatin masses, of two conjugating 

parasites. 
11. Complete union of bodies and nuclei. 
12. 13. Comparative sizes of full-grown forms developed with and without conjugation. 



3fALABIA. 455 

tions of the infection and becomes less frequent as the disease pro- 
gresses, the infection in the human host thereby tending to limit 
itself. 

Several sources of error in the interpretation of these appearances 
have to be considered. The presence of two masses of chromatin 
has been noted in single young parasites. Yet the existence of the 
bodies of two parasites can usually be determined with certainty, 
while some conjugating forms contain three large masses of chromatin 
granules, i. e., when one of the conjugating forms supplies an extra 
granule. The conjugating forms must, therefore, be identified from 
the presence of the bodies as well as the chromatin masses of two 
parasites. 

The death and extrusion of one or of both of the twin parasites 
cannot account for the absence of older, twinned forms, since no traces 
of such extrusion were encountered. Twin parasites sometimes pro- 
ceed to full development without conjugating, but this event is com- 
paratively rare. 

The existence of these three types of full-grown tertian parasites 
naturally suggests that the single, compact form develops into the 
microgametocyte or male flagellating body, the single, ring-shaped 
form developing into the macrogametocyte or female form, and the 
conjugating form into the sporulating body. 

The above observations regarding the existence of three varieties of full- 
grown tertian parasites have recently been verified by Argutinsky, 

The further attempt to trace the younger forms of male and female tertian 
parasites is beset with great uncertainties. The author finds that it is usually 
possible to detect the gradual differentiation of the sexes after the infection 
has progressed through several paroxysms. In these prolonged cases which 
have been allowed to run on without quinine the appearance of the parasites 
is strikingly altered. Small, compact parasites, without rings, become abun- 
dant, but the thin ring forms nevertheless persist ; forms resembling quartan 
parasites appear, and in some of these four to six groups of chromatin granules 
appear in the body. These latter forms seem to be the ones which flagellate, 
and the fact that they appear abundantly only in the later stages of infections 
accounts for the frequent failure to secure flagellating bodies when the blood is 
drawn early in the disease. 



V. THE OCCURRENCE OF PARASITES IN THE CIRCULATION. 

In all well-marked initial attacks of malarial fever the parasite can 
he found in the blood if examined within eighteen hours after the chill. 
The writer found this rule to hold even in patients who were taking 
large doses of quinine, but in one case examined twenty-four hours 
after the chill parasites could not be found during a search of two 
hours through stained specimens. 

In the great majority of cinchonized cases of acute estivo-autumnal 
fever, parasites can be found within a week after the beginning of 
the paroxysm, while crescents may persist for two or three weeks or 
more. In cases treated by quinine the writer found the ameboid 
parasites to largely disappear from the blood on the third day. If 
no crescents appear, the blood then becomes entirely free of para- 



456 ANIMAL PARASITES. 

sites, but usually crescents enter the circulation on or after the fourth 
day and the examination of the blood still continues positive. 

On the other hand, with very mild or with cinchonized cases a pro- 
longed search is sometimes required for the detection of i^arasites. 

In a few relapses of estivo-autumnal infection, examined during 
the chill, the writer had to search thirty-five to fifty minutes before 
discovering a single parasite, and in several other cases only young 
crescents could be found, while if the examination was delayed for 
eighteen to tweny-four hours it was often necessary to search for 
two hours or more. With Nocht's stain this labor would probably 
have been reduced. 

In cases that have not taken quinine, the parasites are usually so 
abundant in well-marked infections that no difficulty whatever is experi- 
enced in determining their presence. 

Yet the well-known tendency of the estivo-autumnal parasite to 
retire from the peripheral blood during the sporulating stage may 
leave the finger blood comparatively free from organisms at certain 
periods of the attack. In the tropics Van der Scheer noted that if the 
blood is examined during the sporulating stage no parasites may be 
found, and that they may appear, in scanty numbers only, after some 
hours' growth. Marchiafava and Bignami also emphasize the fact 
that a negative result may frequently be obtained at the beginning 
of an attack. Likewise in mild tertian infections initial paroxysms 
occur in which very few parasites are present in the blood, and in 
some instances they have been reported as absent altogether. The same 
fact has been observed in connection with experimental infections. 

Nevertheless, the writer believes that in acute malarial fever, even 
when quinine has been administered, parasites can always be found, 
if the blood is examined with care and persistence ivithin eighteen to 
twenty-four hours after the chill. 

In the majority of treated cases the usual phases of development 
of the parasite may be found in diminishing numbers. 

Although Golgi holds that the number of parasites in the periph- 
eral blood is no reliable indication of their total numbers in the 
body, yet the severer cases nearly always show the larger numbers, 
while in mild cases parasites may be very scarce. 

In conditions of coma the blood may contain either rings or cres- 
cents, or both, or tertian parasites. When coma arises in the course 
of the active sporulating cycle, it is almost invariably fatal, and the 
presence of many ameboid parasites in the blood of such cases is an 
extremely unfavorable sign. In most cases of malarial coma, espe- 
cially those of very abrupt onset, or with symptoms of meningitis or 
of localized cortical irritation, crescents only are found in the blood 
and recovery usually follows. 

Jn some cases of coma the ivriter had to search one and two hours 
before finding a single parasite, and has encountered some cases of 
coma and convulsions, in subjects believed to be suffering from 
malaria, in which no parasites could be found in the blood. 

The number of parasites to be found in the blood, when they are 
extensively massed in the gastro-intestinal mucous membrane, heart 



MALARIA. 457 

muscle, brain, etc., has iisaally been considerable. Yet the writer 
encountered a few cases of acute estivo-auturanal infection marked 
by violent bematemesis, in which very few parasites were discovera- 
ble in the blnod. In one case of malarial hematemesis no parasites 
could be found during the first three days of the paroxysm, but on 
the fourth day numerous young crescents appeared. 

Fatal Malaria Without Parasites in the Peripheral Blood. 
The question whether fatal malaria exists without the presence of 
demonstrable parasites in the blood has not yet reached complete 
solution. There can be no doubt, however, that in acute paroxysms, 
fatal on the fourth or fifth day or later, the energetic use of quinine 
may rid the blood of all ameboid bodies, although the patient dies 
from the attack. When the blood is not examined until the third 
day of such attacks the result may be negative. 

Marchiafava and Bignami have described peculiar fatal cases of 
estivo-autumnal infection occurring in debilitated subjects, during 
very hot weather, in which few or no parasites were found in the 
blood and very scanty deposits of pigment were present in the viscera. 
The writer has reported a similar case, in which, however, quinine 
had been administered for some days before the examination of the 
blood. In spite of these apparent exceptions to the rule, the writer 
believes, with Marchiafava and Bignami, that fatal acute walaria 
does not exist loithout the presence of ^parasites in the bloody at least at 
some time during the paroxysm. 

Remittent Malarial Fever. Li remittent malarial fever, persist- 
ing longer than seven days, the writer, in thirty selected cases, found 
only estivo-autumnal rings in eight; crescents alone in eleven; both 
rings and crescents in one; tertian parasites alone in one; double 
infection in one; and no parasites in eight. Initial estivo-autumnal 
attacks often begin with remittent pyrexia, and some relapses may 
show a temperature which requires three days to reach its acme and 
three or four to decline. These cases do not properly fall in the 
class of remittent malarial fever, but they probably illustrate the 
self-limiting tendency of malarial infection. 

In chronic malaria, organisms, principally crescents, are usually to 
be found in the blood when there is fever, but are commonly absent 
during afebrile periods. In one case the writer found crescents in 
the blood four weeks after the last chill, quinine having been con- 
stantly administered. 

Long after parasites have disappeared, scanty pigmented leucocytes 
may be encountered in the blood, but the situations in which their 
discovery proves of value in diagnosis are comparatively rare. 
Their detection is more often of value in cinchonized cases of acute 
fever, in which parasites have disappeared. Pigmented leucocytes 
are most abundant shortly after the chill in relapses of well-estab- 
lished estivo-autumnal infection. 

Since Marchiafava and Bignami admit that in chronic malaria 
properly treated mild paroxysms may fail to reduce the number of 
red cells, and since quinine may reduce or destroy the scanty number 
of parasites ordinarily thrown into the peripheral blood, it is neces- 



458 ANIMAL PARASITES. 

sary to admit that paroxysms may occur in chronic malaria without 
diminution of red cells and without parasites in the blood. 

Yet such cases must be excessively rare and by no means open the 
door to the indiscriminate diagnosis of malaria in obscure fibricula 
without anemia or parasites in the blood. 

Typhoid Fever and Malaria. 

The effect of intercurrent typhoid infection upon the blood in 
malaria is very distinct. The concentration which results in typhoid 
fever becomes at once apparent^ the blood drop appears distinctly 
less fluid, and the Hb and proportion of red cells rise. 

During the first week of the disease sporulation of parasites fre- 
quently continues and organisms may be found in the blood as usual. 
Illustrations of this coincidence of active malaria in the first week 
of typhoid fever are rather numerous in recent literature. After 
the first week, when the typhoid fever has become fully established, active 
sporulation of malarial parasites is extremely rare. 

Until recently there was apparently but one case, reported by W. Oilman 
Thompson, in which active sporulation of the malarial parasite was shown to 
have occurred at the height of the typhoid infection. 

Of many others, collected by Lyon, most prove to be examples of malarial 
paroxysms occurring in the first few days of, or during convalescence from, 
typhoid fever. So rare is the coincidence of parasites in the blood during the 
course of typhoid fever that neither Marchiafava, Bignami, Bacelli, Dock, or 
many others, have ever seen a single case. In 159 cases of typhoid fever, 
nearly all occurring in actively malarious subjects, at Montauk, the writer 
could find no instance in which parasites were present in the blood during the 
second to the fourth weeks of the disease, although several early or convales- 
cent cases suffered active malarial attacks with parasites, always tertian, in the 
blood. Cases of quartan infection associated with typhoid fever are reported 
by Thayer and by Craig. 



VI. THE ACTION OF QUININE ON THE MALARIAL 
PARASITE. 

The action of quinine may be followed in the blood of patients 
treated by this agent, or in fresh specimens to which weak solutions 
of the drug are added. 

By the latter method, when a solution of quinine sulphate, 1 to 
1500, is allowed to mix with blood under a cover-glass, it can be 
seen that most parasites soon cease their ameboid movements, although 
vibratory motion of pigment grains may persist for many hours. 
Most of the parasites contract and remain motionless, but, according to 
Monacho and Panichi, the half-grown parasites often leave the red cell 
and are englobed by phagocytes, while the younger and older forms do 
not emigrate and may long show ameboid movements. These authors 
explain from these facts the inefficacy of quinine in any other than 
the apyretic stage. 

In the blood of patients treated by quinine the parasites often 
disappear rapidly without exhibiting morphological changes. 



MALARIA. 459 

According to Golgi and Mannaberg, the administration of quinine 
soon limits the ameboid activity of all forms and induces fragmenta- 
tion and hydropic changes of many. Golgi describes as ^' quinine 
forms'' certain rounded, immobile bodies with clumped pigment and 
sharp, irregular outline, and deformed segmenting bodies deficient 
in the number of spores. Romanowsky and Mannaberg find that 
many of these segments are lacking in chromatin. In cinchonized 
cases the writer has often encountered half-grown forms numerously 
subdivided and deficient in chromatin. 

Most observers agree that quinine is active only on the young, 
ameboid forms, and hence should be administered a few hours before 
the chill. 

VII. THE MALARIAL ANEMIA. 

There are few conditions which lead so rapidly to such extreme 
oligocythemia as does acute malarial infection. Kelsch, who in 
1875 contributed an exhaustive study of malarial anemia, found that 
an acute initial attack lasting three weeks might reduce the red cells 
to 1,000,000 or even to 500,000. In robust subjects suffering initial 
attacks the loss on the first day sometimes reached 1,000,000 red 
cells, or during the first four days 2,000,000. Dionisi observed a 
reduction of 500,000 cells in twelve hours. In relapses the seizure 
did not cause so great a loss of cells as in first attacks. In prolonged 
cases it was often possible to distinguish three periods in the progress 
of the anemia : (1) During the first three to four days the loss of 
red cells was very rapid (1,500,000 to 2,000,000). (2) During the 
afebrile interval and during the relapse the fall was continuous, but 
much less rapid. The minimum of red cells varied with the char- 
acter of the infection, being lower with estivo-autumnal cases, fre- 
quently falling below 2,000,000, seldom below 1,000,000. (3) When 
the patient became very anemic, relapses reduced the red cells very 
much less than before, but the active regeneration of cells caused 
their numbers to oscillate. So energetic may this reproduction of 
cells become that even an increase, instead of decrease, may be 
observed directly after an attack in anemic subjects. 

Initial attacks of pernicious type cause very marked loss of cells, 
but in relapsing pernicious cases, with severe established anemia, it 
is not uncommon to find the severest general symptoms of the 
paroxysm unaccompanied by demonstrable loss of red cells. 

Marchiafava and Bignami find that there may be destruction of 
red cells without fever in larval malaria. 

In chronic malaria the prolonged infection, poor treatment, and 
bad hygiene commonly reduce the red cells below 2,000,000, but 
some extreme cases show below 1,000,000, Kelsch having one case 
with only 583,000. On the other hand, in favorable subjects, when 
attacks occur at intervals of one month or longer, and are promptly 
stopped by quinine, there may be no reduction of red cells (Marchia- 
fava, Bignami). The writer can find no evidence on which to ex- 
tend this exception to the Hb as w^ell. 



460 ANUIAL PARASITES. 

Id afebrile periods, both between relapses and after subsidence of 
the infection, the anemia may still progress. In fact, the ^Yriter 
foLind this farther progress of post-febrile anemia to be the rule in 
all very severe cases, and sometimes it pressed fatal. Dionisi 
observed a fall from 3,200,000 to 2,300,000 of red cells during the 
first six days of apyrexia, in spite of the use of iron. The regen- 
eration of the blood after benign tertian infections usually begins at 
once, but after all pernicious attacks both the response to iron and 
the progress of regeneration are slower. 

Morphology of Red Cells. In cases of moderate severity the 
usual changes in the red cells of secondary anemia are present. 
Even in the early stages of anemia, polychromasia and granular 
degeneration of red cells are sometimes to be noted, while these 
changes increase steadily as the anemia progresses. 

The grave post-malarial anemias present some very interesting 
forms. Marchiafava and Biguami describe three types, based upon 
the changes in the blood and marrow : 

1 . The red cells exhibit the characters of grave secondary anemia 
with extreme loss of Hb, but no nucleated red cells are present. 
The marrow shows simple atrophy of lymphoid cells and of clusters 
of nucleated red cells. 

2. With the same condition of the blood the usual number of 
nucleated red cells may be found, and there is moderate hyperplasia, 
of physiological character, of the lymphoid marrow. 

3. The red cells exhibit the characters of progressive pernicious 
anemia, with high Hb-index, and with megalocytes and megalo- 
blasts. The marrow suffers typical megaloblastic degeneration. 

The writer's study of blood and marrow in fatal cases supports 
this division of post-malarial anemias. While the ordinary features 
of grave secondary anemia were usually found, there were in the 
writer's Montauk series no less than nineteen cases in which the 
changes of the progressive pernicious type had been established in a 
period not longer than ten weeks. In one of these the parasites 
appeared to have been massed principally in the bone-marrow, where 
their numbers were enormous and instances of multiple infection of 
cells were excessively numerous. There can be no doubt that the 
tendency of the estivo-autumnal parasite to be massed in the bone- 
marrow, in both ameboid (the writer) and crescentic phases (Coun- 
cilman, Bastianelli, Bignami), aud the excessive demands on red- 
cell production arising in the disease, render pernicious malaria an 
extremely favorable condition for this disturbance of the structure 
of the marrow and the development of specific megaloblastic changes. 

In nearly all cases of grave malarial anemia polychromasia is a 
marked feature, and granular degeneration becomes so prominent 
that Plehn and others have even described as a peculiar form of the 
parasite those collections of bluish staining granules which appear 
in many badly degenerated cells. This form of degeneration was 
very pronounced in a fatal case of benign tertian infection reported 
by the writer, in which there was also a remarkable grade of hydre- 
mia, aud, in the kidneys, the lesions of hemoglobinuric fever. 



3IALABIA. 461 

Besides the lesions referable to anemia, or to the toxemia of 
paladism, the infected red cells suffer a peculiar series of changes 
resulting from the presence of the parasite. Changes in the size of 
the cell are nearly constant. The tertian parasite, almost from the 
first, causes swelling of the cell and progressive loss of hemo- 
globin, as indicated by increasing pallor. When harboring two 
or three large tertian parasites the red cell may become enormously 
distended. 

When infected by the quartan or any form of estivo-autumnal 
ameba, the red cell usually shrinks and takes on a peculiar, opaque, 
^' brassy '^ color. This change begins at the moment of infection by 
the young ring and becomes more marked with the growth of the 
para^siie. Marchiafava and Bignami suggest fur this condition the 
appropriate term '^ erythropyknosis.'' These authors believe that 
the pyknosis results in the death of both cell and parasite. 

In many cells infected by any form of parasite, especially the 
estivo-autumnal, the hemoglobin collects in a dense layer about the 
parasite, and achromatic clefts often form in the red cell. (Plate 
XVI., Fig. 13.) 

Fragmentation of the red cell is a rather infrequent result of 
infection by the parasite. 

Bignami has described an increased cohesiveness of the infected 
red cells in estivo-autumnal malaria, and explains thereby the ten- 
dency of infected cells to gather in small visceral capillaries. 

Pathogenesis of Malarial Anemia. In the pathogenesis of 
malarial anemia it is necessary to consider the action of several fac- 
tors. Each infecting parasite probably destroys more or less com- 
pletely the harboring cell, and a certain part of the loss of red cells 
must be referred to this source. Yet Dionisi has shown that there 
is no very close relation between the number of parasites present in 
peripheral blood and the destruction of red cells which results from 
a paroxysm. 

Moreover, the plasmodium does not immediately enter the cell, 
but remains for a time merely attached to its surface, and since 
quinine may cause these extraglobular parasites to abandon the cor- 
puscle, as described by Marchiafava and Bignami, it is probable that 
in many paroxysms, properly treated, the destruction of cells result- 
ing from direct consumption by parasites is very slight. 

Many factors indicate that the post-critical anemia is principally 
referable to globulicidal action of the serum, dependent upon the 
presence of a malarial toxin. Some of these facts are the dispropor- 
tion between the anemia and the number of parasites present ; the 
steady diminution in the loss of cells in the second and third, as 
compared with the first paroxysm ; the further progress of anemia 
in many cases after parasites have disappeared from the blood 
(Dionisi, the writer) or during intervals between paroxysms (Kelsch); 
the occurrence of hemoglobin uric malarial fever, and the increased 
resistance of cells demonstrated by Viola during the progress of 
malarial infection. The writer has pointed out at some length that 
the chief bulk of pigment deposited in viscera is derived from the 



462 ANIMAL PABASITES. 

globulicidal action of the plasma and not from the vegetative func- 
tions of the parasite. 

Increased production of red cells greatly alters the progress of 
malarial anemia, being partly accountable for the smaller losses 
observed after secondary paroxysms, and preserving intact or even 
increasing the numbers of cells after paroxysms in very anemic 
individuals. 

VIII. THE LEUCOCYTOSIS OF MALARIA. 

Most observ^ers have found very little change in the numbers of 
leucocytes in the finger blood during acute malarial attacks of average 
severity. This absence of leucocytosis with a rapidly rising tem- 
perature may be found of considerable corroborative value in the 
diagnosis of malarial fever. 

A slight leucocytosis at the beginning of the paroxysm has been 
noted in some cases by Kelsch, Billings, Vincent, and others, but 
the numbers usually remain below 10,000, while the percentage of 
polynuclear cells is increased. Vincent finds that quinine tends to 
increase the polynuclear leucocytes throughout the entire paroxysm. 
With the falling temperature and during a pyrexia the leucocytes are 
usually distinctly diminished (2000 to 4000), especially the poly- 
nuclear forms, giving a relative lymphocytosis. 

Except during the three to four hours immediately following the 
chill, therefore, malarial blood usually shows a diminished number 
of leucocytes and a distinct relative lymphocytosis. The lympho- 
cytes, small and large, may sometimes become quite numerous, espe- 
cially in well-established cases. This fact accords with the increased 
cellular activity of the lymphoid tissues shown by microscopic 
examination of the viscera. 

Marchiafava and Bignami refer the lymphocytosis to a specific 
chemotactic action, but it seems partly referable to simple mechanical 
factors. 

The percentage of polynuclear cells at the beginning of the attack 
is usually high. Billings found over 80 per cent, in some cases. 
Later these forms diminish and usually fall below 60 per cent. In 
pernicious attacks Bastianelli found below 40 per cent, of poly- 
nuclear cells. 

Bastianelli refers the loss of polynuclear leucocytes to the increased 
phagocytic activity of these cells. Vincent noted a periodical 
decrease in the number of large mononuclear cells which he refers 
to the same process. 

In the severer estivo-autumnal _paroxi/sms many observers have noted 
a distinct leucocytosis (Kelsch, Babes and Georghiu, Ziemann, Burot 
and Legrand). Kelsch found that the leucocytosis of pernicious 
malarial attacks often consists in marked lymphocytosis, which the 
writer also has observed. Bastianelli and Bignami show that in 
addition to various inflammatory complications leucocytosis in perni- 
cious malaria may result from rapidly progressive anemia. They 
find it to be of frequent occurrence in hemoglobinuric fever, and in 



3fALABIA. 463 

cases attended with severe diarrhea. Pleho, however, found no 
leucocytosis in most of his cases of hemoglobinuria. The extent of 
the leucocytosis varies between 10,000 and 35,000 cells, the latter 
number having been observed by Kelsch shortly before death in a 
comatose patient. Usually the leucocytosis in pernicious attacks is 
much lower, and many attacks fail to cause any distinct increase. 

The presence of eosinophile cells may be noted in most cases of 
malarial fever, and these cells are usually increased in number during 
afebrile periods. Grawitz rightly regards this feature as of diag- 
nostic importance, as in most diseases likely to be confused with 
malaria eosinophile cells are long absent or scarce. Bastianelli and 
Bignami found that eosinophile cells diminish during the paroxysm 
and increase during apyrexia, while the blood is regenerating. In 
two cases of pernicious malaria, with many parasites, they found 
many mononuclear leucocytes and a very few eosinophile myelocytes, 
similar to those seen in myelogenous leukemia. Neutrophile myelo- 
cytes are often present in small numbers. 

In chronic malaria Kelsch found the leucocytes usually subnormal 
in numbers, but in one of thirty-three cases there was transient 
leucocytosis. 

Pigmented leucocytes are seen in the majority of cases, most abun- 
dantly in the severe and long-established fevers. They are found 
in nearly all fatal cases, but the writer found them most abundant 
in a case which recovered. It appears that the pigmented leuco- 
cytes are more closely related to the severity of the antecedent 
paroxysms than to the extent of the pigment deposits in the viscera. 

They are most abundant during and shortly after the febrile 
period, but are often found in afebrile cases and after parasites have 
disappeared from the blood. The phagocytic cells seen in the blood 
include mononuclear and polynuclear leucocytes and endothelial cells. 
The large and small mononuclear cells are most often found to con- 
tain pigment or parasites, but in a few cases, for reasons not clear, 
large numbers of polynuclear leucocytes are found harboring rosettes, 
other forms of parasites, and pigment. In a few cases very large 
endothelial macrophages may be found in the blood, containing para- 
sites in all stages of degeneration. 

The objects englobed by phagocytes, as seen in the circulation, 
include : (1) Parasites, free or enclosed in red cells. (2) Pigment 
elaborated by parasites, usually in small clumps, sometimes in large 
masses, (3) Hematoidin derived from the destruction of red cells. 
(4) Hemosiderin derived from the detritus of red cells. (5) Intact 
or broken red cells. (6) Other leucocytes. Crystalline pigment is 
often seen in leucocytes in sections of tissues, but never in the circu- 
lating blood during life. 

The degenerative changes in phagocytic leucocytes mentioned by 
Bastianelli and Bignami, including vacuolation and diminished 
staining capacity of nuclei, have been noted by the writer in many 
severe cases. The number of vacuolated leucocytes found in the 
blood is considerable and sometimes very large. Fatty degeneration 
the writer has been unable to demonstrate. 



464 ANUIAL PARASITES. 

From a comparison of the phenomena of phagocytosis in the cir- 
culating blood with those seen in the viscera of fatal cases, it is 
evident that the phagocytic function of the leucocytes in malaria is 
very subordinate to that of the visceral phagocytes in all but a few 
exceptional cases. 

Bibliography, 

The literature on malaria has become so extensive that it has been 
thought best to omit from the present list any references except to 
important original studies, and to a few recent contributions. 

A most serviceable bibliography, alphabetically arranged, will be 
found in Manuaberg's monograph, ^^Die Malaria Krankheiten,^^ in 
NothnageVs Spec. Path., 11. Bd., 11. Th. Wien, A. Holder, 1899. 

Barbacci's lists, Cent. f. Fcdh., 1899, p. 64, are also very com- 
plete and more recent. 

Many articles up to 1895 will be found more accessible to Ameri- 
can readers in the references given by Thayer and Hewetson, The 
Malarial Fevers of Baltimore, Johns Hopkins Press, 1895. 

Babes, Georghiu. Etudes sur les differentes formes dii parasite. Annal. de 
I'Institut de pathol. de Bucharest, 1890. Cited bv Barbacci, Cent. f. Path., 
1899. Archiv. de med. nav., 1893, Mar. 

Barhacci. Xeuere Arbeiten ueber Malaria, 1892-7, Cent. f. Path., 1899, p. 64. 

Bastianelli, Bignami. Studi suUa infezione malarica, Bull. d. R. Ac. med. di 
Roma, 1893, 1894. Archiv. Ital. d. Biol., 1895, XXIIL, III. 

Bignami. Recherche sull'anat. d. perniciose, Atti. d. R. Ac. med. di Roma, 
1890, vol. V. Studi sull'anat. patol. d. infez. malar, cronica, Atti. d. R. Ac. 
Roma, 1893. Inoculation Theorv of Malarial Infection, Lancet, 1898, II., pp. 
1461, 1541. 

Bignami, Bastianelli. Structure of Flagellate Bodies, Lancet, 1898, II., p. 1620. 

Bignami, Dionisi. Le anemie postmalarische, XL Internat. Cong., Rome, 
1894. 

Billings. Johns Hopkins Bulletin, 1894, p. 89. 

Burot, Legrand. Therapeutique du paludisme, Paris, Balliere et Fils, 1897. 

Celli, Guarnieri. Aetiologie der Malariainfection, Fort. d. Med., 1889, p. 521. 

Councilman. Fort. d. Med., 1888, Xos. 12-13. 

Craig. Philadelphia Med. Jour., vol. iii. p. 1369. 

Dock. Pernicious Malarial Fever, Amer. Jour. Med. Sci., 1894, vol. Q\\i. p. 379. 

Ewing. Results of Blood Examinations at Camp Wickoff. X. Y. Med. Jour., 
1899, vol. Ixix. pp. 114-149. ^ Jour, of Exper. Med., vols, v., vi. X. Y. Med. 
Jour., vol. Ixxiv. p. 145. 

Futcher, Lazear. Johns Hopkins Bulletin, 1899, vol. x. p. 70. 

Gautier. Malariastudien im Kaucasus, Zeit. f. Hvgiene, 1898, Bd. 28, p. 439. 

Golgi. Fort. d. Med., 1886, Xo. 17. Fort. d. Med., 1889, Xo. 3. Ueber die 
romischen Sommer-herbstfieber, Deut. med. Woch., 1894, Xos. 13, 14. 

Grassi, Bignami, Bastianelli. Archiv. Ital. de Biol., 1899, T. 31, p. 259. Archiv. 
Ital. de Biol., 1899, T. 32, p. 46. 

Grassi, Feletti. Cent. f. Bact., 1890, 1891, Xos. 12-16. 

Guarnieri. Atti. d. R. Accad. med. di Roma, 1887. 

Kelsch. Archiv d. Physiol., 1870, p. 490; 1875, p. 690. 

Kelsch, Kiener. Maladies des pays chauds, Paris, Balliere et Fils, 1889. 

Laveran. Traite du Paludisme, Paris, 1898, Masson et Cie. 

Leukowicz. Cent. f. Bact., 1897, p. 129. 

Lyon. Amer. Jour. Med. Sci., vol. CKxii. p. 25. 

MacCallum. On the Hematozoan Infection of Birds, Jour, of Exper. Med., 
1898, p. 117. 

Mannaherg. Die Malaria Krankheiten, Wien, A. Holder, 1899. 

Manson. Lancet, 1896, a^oI. ii. p. 1715. 

Marchiafava. XL Internat. Cong. Rome, vol. ii. p. 225. 



MALAEIA. 465 

Marchiafava, Bignami. Estivo-autiimnal Malaria (translation by Sydenham 
Soc, 1894). Ueber die Varietaten der Malariaparasiten, Deut. med. Woch., 1892, 
Nos. 51-52. 2 Twentieth Century Practice, 1900. 

Marchiafava, Celli. Bull. d. R. Ac. di Roma, 1887. Atti. d. R. Ac. di Roma, 
1887, vol. iii. Arcliiv. Ital. de Biol., 1888, fasc. iii. Atti. R. Acad. med. 
Roma, 1890-91. 

Marchoux. Le paludisme au Senegal, Annal. de I'lnstitut Pasteur, 1897, No. 8. 

Marshall. Lancet, 1896, vol. ii. p. 1187. 

Maurer. Cent. f. Bact., Bd. 32, p. 695. 

Michaelis. Cent. f. Bact., Bd. 29, p. 763. 

Monacho. Panichi. Cent. f. Bact., Bd. 27, p. 630. 

Nocht. Zur Farbung der Malariaparasiten, Cent. f. Bact., 1898, p. 839; 1899, 
p. 17. 

Okintschitz. Cited by Barbacci. 

Plehn. Schwarzwasserfieber an der Afrikanische Westkiiste, Deut. med. Woch., 
1895, Nos. 25-28. Beitrage zur Kenntniss der trop. Malaria, Berlin, Hirschwald, 
1896. 

Romanowsky. St. Petersburg med. Woch., 1891, Nos. 34, 35. 

Ross. Du role des moustiques dans le paludisme, Annal. de I'lnstitut Pasteur, 
1899, pp. 251, 289. Brit. Med. Jour., 1897, II., pp. 1179, 1786; 1898, 1., pp. 550, 
1575, 1607. 

Saccharoff. Recherch. sur le parasite des fievres palustres irreg., Annal. de 
I'lnstitut Pasteur, 1891, No. 5. Cited by Barbacci (1893). Ueber der Einfluss 
der Kalte auf, . . . der Malariaparasiten, Cent. f. Bact., 1894, Nos. 5, 6. Ueber 
die selbstandige Bewegung der Chrosmosomen bei Malariaparasiten, Cent, f . Bact., 
1895, Nos. 12, 13. 

Smith. Etiology of Texas Cattle Fever, N. Y. Med. Jour., 1895, vol. Ixx. p. 
47. 

Solley, Carter. Presbyterian Hospital Report, 1899 

Thayer, Hewetson. Malarial Fevers of Baltimore, Johns Hopkins Press, Balti- 
more, 1895. 

Thompson. Trans. Assoc. Amer. Phys., 1894. 

Van der Scheer. Ueber tropische Malaria, Virchow's Archiv, 1895, Bd. 139. 

Vincent. Annal. de I'lnstitut Pasteur, 1897, No. 12. 

Wright. Jour, of Med. Research, vol. vii. p. 138. 

Ziemann. Ueber Malaria u. andere Blutparasiten, Jena, G. Fischer, 1898. 
2 Cent f. Bact., 1897, Bd. 22, Nos. 17, 18; 1896, p. 653. 



30 



CHAPTER XXIV. 

EELAPSING FEVER. 

Morphology of the Parasite. The parasite of relapsing fever, 
discovered in the fresh blood by Obermeier in 1873, is a spirillum 
about 16// to 40/i in length, being subject to considerable variations 
in size. It is very thin, sharply contoured, structureless, and resem- 
bles a curled fibrin-fibril. Soudakiewitch described irregularly con- 
toured spirilla and some with a granular swelling at one end which 
he regarded as a spore. Several parasites may be twisted together, 
and occasionally considerable numbers are found in a granular-look- 
ing mass. These nests are supposed to form in stagnating blood. 
Orth and Ponfick failed to find the spirilla in the blood of the cadaver, 
but in the fresh blood movements may be observed for two to eight 

Fig. 37. 




Spirillum of Obermeier in human blood. Carbolic fuchsin. Magnified 1000 diameters. 
(From Slater and Spitta's Atlas.; 

hours. Sometimes they are motionless (Engel). Albrecht saw a 
considerable increase in their numbers in specimens that had stood 
six hours, and in one of Lachmann' s cases a marked increase appeared 
to occur in the cadaver. 

Bodies of Uncertain Character Described in the Blood of Recurrent 
Fever. There has always existed a belief that forms of the parasite 
other than the spirillum must occur in the blood, and various bodies 
believed to represent developmental stages of the parasite have been 
described. 

Sarnow and v. Jaksch found, during the afebrile interval, spore- 
like bodies resembling cocci which became very numerous before the 



EELAPSING FEVEB, 467 

chill. V. Jaksch claimed to have seen these bodies develop into 
tvpical spirilla. Larger protoplasmic masses of varying structure 
were described by Obermeier, Ponfick, Blisener, Litten, Albrecht, 
and others. Heidenreich described them minutely, as compact, or 
vacuolated, variously subdivided, of different sizes, containing gran- 
ules, fat droplets, or red blood cells. Saceharoff also described such 
masses, findiDg them most abundant in the afebrile period, some 
being twenty times the diameter of a red cell. He claimed to have 
observed the formation of flagella and their separation from the mass. 
Some of these flagella entered red cells and developed into similar, 
large, protoplasmic masses, after the manner of the malarial crescent. 
From the nucleus of the parent mass other slender flagella were pro- 
truded, which, on becoming free, circulated in the plasma as the 
spirilla. Heidenreich regarded these observations of Saccharoff as 
of great importance in the biological study of the parasite, but they 
do not appear to have been followed up. 

Method of Demonstration. In dry specimens of blood the 
spirilla stain well with aniline dyes, and Karlinski succeeded in 
demonstrating flagella with some individuals. Concentrated solution 
of methylene blue stains all spirilla in two to five minutes. 

Examination in the fresh condition yields interesting information 
regarding the movements of the spirilla, and should be employed to 
demonstrate their motility, but not for the determination of their 
presence in doubtful cases. 

Occurrence in the Blood. Heidenreich found a few spirilla in 
the blood twenty-four hours before the chilly but most observers have 
failed to find any at this time. 

With the rise in temperature the parasites are usually to be found 
in small numbers, one parasite in ten to twenty fields of the micro- 
scope (MoczLitkowsky). They are always to be found on the second 
day (Blisener), and thereafter rapidly increase, often to enormous 
numbers (e. g., twenty to thirty in one field). Yet Engel claimed 
that even during high fever the parasites cannot always be found in the 
blood. Daring defervescence the numbers steadily diminish, and in 
the afebrile periods may entirely disappear, but Naunyn, Birch- 
Hirschfeld, Litten, and Unterberger found an occasional parasite at 
varying intervals during the afebrile period. 

With each succeeding paroxysm the spirilla are apt to appear in 
increasing numbers, but there is no strict parallel between their 
abundance in the blood and the height of the temperature, while it 
has been shown that their numbers vary both from day to day, and 
in different parts of the circulation. 

Artificial Cultivation. Heidenreich kept the spirilla alive for 
one hundred and eighty days in defibrinated blood. The single 
cultures were preserved longest at a temperature of 18° to 21° C., 
but at febrile temperature they soon became motionless. They were 
very sensitive to oxygen, CO^, saliva, ascitic fluid, urine, and to 
moderate variations in the quantity of salts in the fluid. Heiden- 
reich and Kannenberg believe this sensitiveness to slight changes in 
the temperature and osmotic tension of the surrounding medium 



468 ANIMAL PARASITES. 

explains the short life of the parasite in the human body, but Moczut- 
kowsky found them to resist a temperature of 48° C. 

Multiplication in artificial media has been successful only in the 
hands of Koch, but the method was not fully described. Inocula- 
tion in monkeys was first successfully performed by Carter and Koch, 
the animals exhibiting the symptoms of the disease and their blood 
containiug numerous spirilla. Obermeier and Engel had negative 
results from the injection of blood into dogs, rabbits, and guinea- 
pigs. Moczutkowsky performed several successful inoculations in 
men. Very interesting results were obtained by Albrecht, who 
kept in a moist chamber specimens of blood drawn when the spirilla 
had temporarily disappeared. After five to six days, in some speci- 
mens, the spirochetes appeared in large numbers. Albrecht describes 
what he believes to be the intermediate stage of development of the 
parasite. 

Destruction of the spirilla in the blood is accomplished, according 
to Wernich, by means of the products elaborated by the parasites 
themselves; according to Heidenreich, through the great susceptibility 
of the germ to changes in temperature and chemical composition of 
the blood; according to Moczutkowsky, through concentration of the 
blood, the density of which, however, diminishes during the par- 
oxysm (Trautgott), and according to Metchnikoff and Soudakiewitch, 
by phagocytosis. 

The paralyzant effects upon the spirilla of the serum of patients 
who have recovered from the disease indicate that specific bacteri- 
cidal principles are developed in the blood (Mamourofsky, Gabrils- 
chewsky). Yet the studies of Soudakiewitch on phagocytosis in 
relapsing fever are among the most important on which the doctrine 
of phagocytosis is founded, and have placed beyond doubt its impor- 
tance in the destruction of the spirillum of Obermeier. 

Changes in Red Cells. Boeckman reported that the red cells 
sink during and for one to two days after the attack, increasing 
somewhat in the afebrile periods. Halla counted 4,600,000 red 
cells on the nineteenth day of the illness, and found 50 per cent, of 
Hb in a severe case. 

Leucocytes. Laptschinsky, Heidenreich, and Boeckman all noted 
considerable leucocytosis, most marked just after the crisis. Lapts- 
chinsky mentioned the presence of a very large number of coarsely 
granular leucocytes. 

Bilious Typhoid Fever (Griesinger). In 1854 Griesinger 
described under the term typhus ideroides a disease which occurred 
in epidemic form in Cairo, and sporadic cases of which still persist 
in Smyrna. Moczutkowsky, Karlinsky, Heidenreich, and others 
fully demonstrated the nature of this malady by finding in every 
case large numbers of the spirillum of Obermeier. 

Serum Diagnosis. Gabritschewsky found that when the blood 
of a patient who had just recovered from relapsing fever was added 
to a specimen of blood containing spirilla and kept in the thermostat, 
the parasites became motionless within one-half to one hour. 

Loewenthal applied this fact to the diagnosis of relapsing fever 



JRELAFSING FEVER. 469 

during the apyretic interval when parasites are absent from the blood. 
The specific reaction was most marked immediately after the par- 
oxysm, diminished steadily, and sometimes became inappreciable, 
just before the next chill. In cases which had successfully over- 
come the infection the reaction persisted longer, and Loewenthal 
claimed that if it persisted as late as the seventh day in sufficient 
intensity to immobilize the spirilla in one hour no further relapses 
ever occurred, otherwise relapses invariably followed. There are 
several uncertainties conuected with the work of Loewenthal, and his 
claims require confirmation. 

Sawtschenkow and Melkich find that the bactericidal action of the 
blood in relapsing fever does not vary with the leucocytes, but 
increases after the acme of leucocytosis. Heating to 64° C. for one- 
half hour destroys the immunizing properties of the serum, but does 
not enfeeble its agglutinating properties. 

Bibliography. 

Relapsing Fever. 

Alhrecht. Deut. Archiv f. klin. Med., Bd. 29, p. 77. 
Birch-Hirschfeld. Archiv f. klin. Med., Bd. 13, p. 346. 
Blisener. Diss. Berlin, 1873. 

Boeckman. Deut. Archiv f. klin. Med., Bd. 29, p. 481. 
Carter. Brit. Med. Jour., Oct. 1. 1881. 
Engel. Berl. klin. Woch., 1873, p. 409. 
Gabritschewsky . Annal. de I'lnstitut Pasteur, 1896, p. 630. 
Griesinger. Archiv f. physiol. Heilk., 1854, p. 554. 

Heidenreich. Untersuch. u. d. Parasit. d. Ruckfallstyphus, Berlin, 1877 
V. Jaksch. Klin. Diagnostik. 
Kannenherg. Charite-Annalen, 1878, p. 235. 
Karlinski. Fort. d. Med., 1891, p. 456. 
Koch. Mitt. a. d. kais. Gesundheitsamte, Bd. 1, p, 40, 
Lachman. Deut. Archiv f. klin. Med., Bd. 27. 
Laptschinsky . Cent. f. med. Wissen., 1875, p. 36. 
Litten. Deut. Archiv f. klin. Med., Bd. 13, p. 155. 
Loewenthal. Deut. med. Woch., 1897, p. 560. 
Mamourofsky. Revue medicale, 1894, p. 20. 
Metchnikoff. Virchow's Archiv, Bd. 109, p. 177. 

Moczutkowsky. Deut. Archiv f. klin. Med., Bd. 24, p. 80; Bd. 30, p. 165. 
Naunyn. Berl. klin. Woch., 1874, p. 81. 

Obermeier. Cent. f. med. Wissen., 1873, No. 10. Berl. klin. Woch., 1873, p. 
391. ' ' f 

Orth. Path, anat., Diagnose. 

Ponftck. Cent. f. med. Wissen., 1874, No. 25. 

Saccharoff. Cent. f. Bact., 1889, Bd. 5, p. 420. 

Sarnow. Diss. Leipzig, 1882. 

Sawtchenchow, Melkich. Annal. de I'lnstitut Pasteur, 1901, p. 521. 

Soudakiewitch. Annal. de I'lnstitut Pasteur, 1891, p. 545 

Trautgott. Cited by Kiliani, Twentieth Cent. Practice, vol. xvi. p. 477. 

Unterberger. Jahrbuch f. Kinderheilk., Bd. 10. 

Wernich Berl. klin. Woch., 1880, No. 54. 



CHAPTER XXV. 

MISCELLANEOUS PARASITIC DISEASES. 
TRICHINA SPIRALIS. 

The relation of trichinosis to the blood is found principally in 
the extreme degree of eosinophilia which marks the condition. 

The red cells, in trichinosis, do not suffer greatly. x4fter recovery 
from the disease, when the disturbing effects of fever are eliminated, 
a moderate grade of chlorotic anemia is usually to be noted. Thayer 
reports 4,300,000 red cells and 68 per cent, of Hb in a recent case. 
In the majority of active cases the red cells are slightly or not at all 
diminished, while the effects of cyanosis in concentrating the blood 
have several times been encountered. 

Leucocytes. All cases have shown leucocytosis, ranging from a 
slight increase to 35, 700 cells, recorded by Brown. This leucocy- 
tosis is usually in proportion to the severity of the disease (Blumer 
and Xeuman), and persists in moderate degree for weeks or months. 
It may be more or less intermittent. 

The leucocytosis is a natural accompaniment of the exudative myositis 
caused by the parasite. Brown observed a considerable deposit of oxyphile 
cells in the neighborhood of some of the cysts and concluded that the trans- 
formation of neutrophile cells occurs in the muscles and blood stream, a view 
which cannot at present be accepted. In Lambert and Brooks' case the 
writer could fiad no evidence of the transformation of neutrophile into eosino- 
phile granules, although some of the eosinophile granules were unusually 
small. In the muscles the writer found a very scanty deposit of eosinophile 
cells, the majority of new cells being poly nuclear or mononuclear leucocytes or 
proliferated muscle and endothelial cells. 

Eosinophilia. Although the presence of marked eosinophilia in 
various forms of intestinal parasitism was fully demonstrated by 
Bucklers in 1894, its occurrence in trichinosis was not reported until 
Thayer and Brown, in 1897, encountered a well-marked case. Since 
then numerous confirmatory reports have been contributed by Cabot, 
Gwyu, Atkinson, Stump, Blumer, Xeuman, Lambert and Brooks, 
and others. 

From these observations it appears that trichinosis is invariably 
accompanied by marked eosinophilia. Yet while the leucocytosis is 
usually in proportion to the severity of the disease, the eosinophilia 
bears no such constant relation. One of Blumer's mild cases showed 50 
per cent, of eosinophiles, and a recovering case, reported by Brooks, 
gave 83 per cent. In Kerr's three cases eosinophilia was persist- 
ently high, once reaching 86 per cent, of 20,000 cells. Proportions 
of 40 to 60 per cent, are usually found, but at some periods they 



MISCELLANEOUS PARASITIC DISEASES. 



471 



may fall to 7 to 10 per cent. It was reserved for Da Costa to record 
a case of extreme infection without eosinophilia on repeated exami- 
nations. In this case the muscle tissue was found to be swarming 
with trichinae and rich in eosinophile cells, while the blood gave 
12,000 leucocytes and 0.5 per cent, of eosinophiles. As a rule, 
when the neutrophile cells are abundant the eosinopliile are scanty, 
and vice versa. Cabot reports as high as 6 per cent, of myelocytes 
in this disease. The eosinophilia appears to be very persistent, 15 
per cent, of these cells remaining after four and one-half months in 
Stump's case, and 34.7 per cent, after five months in one of Brown's 
cases. 



Fig. 



Fig. 39. 





Trichina spiralis (magnified), a, female; b, 
male ; c, embryo. (From Sahli.) 



Male bilharzia, with female partly enclosea in 
gynecophoric canal. (Lortetand Vialleton. 



The constancy and extent of eosinophilia in trichinosis render the 
examination of the blood of great value in the diagnosis of this infec- 
tion. It seems possible that mild cases have been overlooked in the 
past which might have been detected by this means. 

Yet while the presence of marked eosinophilia should always sug- 
gest the possibility of trichinosis, there is no great pathognomonic 
value attached to the symptom, since equal grades of eosinophilia 
have long been shown to accompany a great many other condi- 
tions. ^ The least that must be required in the diagnosis is an 
unequivocal clinical course, in which case the examination of the 
blood is secondary corroborative evidence, or the demonstration of 



472 



ANUIAL PARASITES. 



eosinopWlia in the blood, aod trichinae or exudative inflammation in 
the muscles (Stump, Brooks). 

In the New York Hospital cases have recently been encountered 
with and without prostration and fever, but with transient edema 
of the face and moderate eosinophilia. In the mildest of these cases 
a minute portion of the biceps muscle yielded live trichinae. This 
edema, which appears to be a very important diagnostic symptom, 
was very transient, lasting only a few hours at the beginning of 
symptoms. 

DISTOMA (BILHARZIA) HEMATOBIUM. 

This is a nematode worm, very abundant in Egypt and South 
Africa, and occasionally found in the United States. The male is 

Fig. 40. 




Blood clot in urine, showing ova of biiharzia (slightly magnified). 
(After Lortet and Vialleton.) 



whitish, 7 mm. to 16 mm. long; the female, often found in the 
gynecophoric canal of the male, is darker and finer and reaches 20 
mm. in length. These worms inhabit the smaller veins of the portal 
system, where as many as 300 individuals have been found. 

The ova, in the encysted stage, have the shape of a melon seed, 
Y^Q- to ^^-Q inch in length, with a transparent shell in which the 
ciliated embryo may be seen. These ova are deposited in the capil- 
lary plexuses, where they cause stasis and hemorrhages. They are 
found in the wall of the bladder, rectum, kidney, ureter, and in the 
lungs, but never in the spleen, pancreas, or stomach (Lortet, Vial- 



MISCELLANEOUS PARASITIC DISEASES. 



473 



leton). Kartulis found them widely distributed, occurring even in 
tumors of the bladder, which frequently arise in these subjects. He 
could never find them in the hearths blood. The ova are usually 
detected, clinically, in the blood clots which pass with the urine, 
where their appearance is somewhat characteristic. 

The life-history and mode of infection have only partly been traced. 

Severe grades of anemia sometimes follow the repeated attacks of 
cystitis and hematuria. 

ASCARIS LUMBRICOIDES (OXYURIS) (TENIA). 

Demme reports a case of fatal anemia in a child with 1,650,000 
red cells, and large masses of ascarides in the intestines. Bucklers 
found 41 per cent, of Hb in one case, and in a series of cases counted 
various proportions of eosinophile cells, maximum 12.25 per cent. 
In a case of oxyuris he found 16 per cent, of eosinophiles, while in 
mixed infections of oxyuris and ascaris the proportions were some- 
what higher, maximum 19.31 per cent. In cases of tenia, eosinophilia 
was moderate or absent, the maximum being 10.25 per cent. 

Solley reports two interesting cases of ascarides, in one of which 
33 per cent, of 7000 white cells were eosinophile. In the other the 
patient suffered from pernicious anemia with very large numbers 
(300 to 35,000) of nucleated red cells, and a distinct normoblastic 
crisis was observed. 

Runeberg has observed one case of pernicious anemia in a patient 
infected by the oxyuris. 

ANGUILLULA STERCORALIS (INTESTINALIS). 

Anguillula stercoralis is a nematode worm which is often asso- 
ciated with ankylostoma. It measures 2.2 mm. in length, while the 



Fig. 41. 




Anguillula intestinalis, female and embryo. (Golgl and Monti.) 

embryos are but 0.2 to 0.3 mm. long. The ova develop very rapidly 
in the intestinal tract, and are passed in the stool only after catharsis. 
They were believed by Normand, their discoverer, and by Davaiue 
and Perroncito to be the cause of a severe form of diarrhea prevalent 
in Cochin China, and often accompanied by severe anemia. Mansou, 



474 ANIMAL PARASITES. 

however, claims that they are ioDOcuous, although Davaine found 
them present in great numbers in cases of anemia. 

Lately Teissier reported the discovery of numerous embryos of 
anguillula in the blood of a case of intermittent fever. With the 
expulsion of the worms from the intestine the fever declined and the 
embryos disappeared from the blood. Bucklers reported 13.5 per 
cent, of eosinophile cells in the blood of one case. 



ANKYLOSTOMA DUODENALE. 

This parasite is of nearly universal distribution in tropical latitudes, 
and, although located in the small intestine, secures its nourishment 
from the blood of the host. It much resembles the ordinary pin worm 
(oxyuris), being cylindrical in form, 6 mm. to 11 mm. by 0.4 mm. to 
0.5 mm. in dimensions (the females are somewhat shorter and 
thicker), and being white when alive, gray when dead, and reddish 
brown when full of blood. The head is provided with four hooks, by 
which the parasite attaches itself firmly to the mucous membrane. 
The ova as found in the feces are similar in general appearance to 
those of bothriocephalus, but the yolk globules are larger. 

The extracorporeal development passes through several phases, 
infection occurring by the transfer of earth containing the encysted 
embryos to the stomach of the host. Leichtenstern has shown that 
anhylostoma does not require a second host for the completion of its 
cycle, but may pass from man to man after a short period of extra- 
corporeal development. Ova appear in the stools within four to five 
weeks after the ingestion of the embryos. 

Although discovered in 1838 by Dubini, its pathological importance was first 
established by Griesinger, who, in 1854, showed it to be the specific agent in 
the so-called '' Egyptian chlorosis." Later it was identified as the cause of 
many forms of tropical anemia, especially by Wucherer in Brazil, andPerron- 
cito in Italy. Through the studies of Grassi, Cinisella, and others, anky- 
lostomiasis became known in Italy as the specific cause of the anemia of 
mountaineers, tunnel workers, etc., while the discovery by Sonderegger, and 
others, of the same parasite in the St. Gothard epidemic, called general atten- 
tion to the subject. In Germany the anemia which had long since been 
described by Heisse among brickmakers was placed in the same class from the 
discovery of the ankylostoma by Menche, in an epidemic at Cologne. From 
these sources the course of infection was traced to nearly all parts of middle 
Europe. Isolated cases are still occasionally described from these regions, 
while the disease remains epidemic in many tropical regions. The disease is 
indigenous in the United States. 

Mode of Infection. The chief source of infection is by the trans- 
fer of the embryos to the mouth by dirty hands. The rapid spread 
of the disease and its contagiousness are explained by the rapid 
development of the ovum, which, on leaving the host, reaches the 
encysted form, capable of further infection, within one or two weeks 
(Manson). A second mode of infection, pointed out by v. Schopf 
and demonstrated experimentally, consists in the inhalation of the 
encysted larvae in dust. In the alkaline fluids of the duodenum the 
chitinous hull of the embryo is dissolved, when the young worm 



BIISCELLANEOUS PARASITIC DISEASES. 475 

promptly attaches itself to the mucosa. Only the plasma appears 
to be utilized in the nourishment of the parasite, as undissolved red 
cells are extruded from the anus (Leichtenstern^). The number of 
worms found in cadavers varies greatly, but often several hundred 
are to be counted, the males being one-third as numerous as the 
females. Leichtenstern^ connted as many as 3000 in a fatal case. 

Pathogenic Action. The essential action of the parasite in the 
causation of anemia has been repeatedly shown by the prompt 
recovery which has followed its expulsion. Yet the anemia has 
progressed in some instances after the expulsion of the worm, and a 
cure cannot be assured in the very advanced stages of the disease. 
The frequent losses of blood are undoubtedly a chief cause of anemia, 
since the parasite, though small, is very prodigal of the blood, and 
the severest cases usually show most parasites. Yet there have been 
many exceptions to this rule, and some fatal cases having shown 
very few parasites, like that of Leichtenstern, in which only twenty- 
four were found, it has been held that a condition of specific intedinal 
intoxication is established by the growth of the worms. The evidence 
on which this theory is based is, however, very incomplete. Lus- 
sana found that the urine in ankylostomiasis, when injected into 
rabbits, dissolves red cells much more actively than does normal 
urine, and Bohland demonstrated that there is a very active destruc- 
tion of albumins in this form of anemia. 

In Sand withes remarkable experience the red cells averaged 
1,300,000, while the Hb even with very low numbers of red cells 
was much reduced, average 26 per cent. The condition of the blood 
was, therefore, not strictly in accord with that of progressive perni- 
cious anemia, while the pathological lesions found at autopsy also 
varied from the typical features of pernicious anemia. In Ashford^s 
report, among important features, are a record of 668,888 red cells, 
excessive reduction in Hb with extreme anemia, and the rapid 
progress of the anemia followed by rapid improvement on the expul- 
sion of the worms. The usual degenerative changes in the red cells 
have been uniformly present in severe cases. Ashford found rather 
few nucleated red cells as compared with idiopathic anemia, and 
always a predominance of normoblasts. 

Changes in the Blood. The anemia passes more or less rapidly 
through milder stages, and in severe cases reaches the pernicious 
grade. 

In the majority of instances the condition observed is one of chlo- 
rotic anemia, with moderate loss of red cells and very marked loss 
of Hb. In cases with over 4,000,000 red cells Zappert found 50, 
40, and 30 per cent, of Hb. In many cases, however, the changes 
in the blood are more severe, and the presence of megalocytes, 
microcytes, megaloblasts, and increased Hb-index renders the con- 
dition identical with cryptogenic pernicious anemia. 

In the progress of the anemia Leichtenstern distinguished two stages, 
which can be most clearly traced when the infection is very active. There 
is an initial stage of acute anemia when the parasites are actively changing 
their location in the intestine, which is marked clinically by colicky pains 



476 ANIMAL PARASITES. 

and bloody diarrhea. Later comes the stage of chronic anemia, maintained 
by the steady consumption of blood by the parasites as well as by some 
intoxication. 

Leucocytosis of moderate grade is frequently observed, especially 
during the early stages. That it is absent in the majority of uncom- 
plicated cases is apparent in the study by Ashford, who is inclined 
to refer any lencocytosis in the disease to complications. Bucklers 
found 20,000 white cells in an early case, and many others have 
reported intermediate grades of leucocytosis. In the severe grades 
of anemia the leucocytes are usually diminished, Zappert^ finding 
only 1800 in one instance, and Ashford 1500 in his severest case. 
The eosinophile cells are nearly always in excess and sometimes reach 
an extreme proportion. This fact was first noted by Miiller and 
Rieder, and Zappert,^ but a very high proportion (53 per cent.) was 
first recorded by Bucklers, while Leichtenstern^ saw cases with 62 
and 72 per cent. 

BOTHRIOCEPHALUS LATUS. 

Description of Parasite. This tapeworm measures from six to 
ten metres, occasionally twelve to sixteen metres in length, and is 
distinguished from all other intestinal parasites by the combination 
of a very broad segment and a pigmented uterus which occupies a 
central position in the segment. The head has neither rostellum nor 
booklets. The eggs are oval, 0.05 mm. by 0.035 mm., with a rather 
thin, double-contoured shell, at one end of which is a cap, while the 
undeveloped embryo is found to consist of a number of large, yel- 
lowish globules. Infection occurs by eating uncooked fish, which 
is the intermediate host. This practice is confined largely to the 
French, Swiss, and Italian lakes, the shores of the Baltic and North 
seas, and Japan, but owing to the long life of the parasite infected 
subjects have been encountered in many other countries. The writer 
obtained four adult specimens from a healthy Swede in New York 
City who had not been out of the State for eleven years. 

History and Pathogenesis. The first important inroad made 
upon the group of idiopathic pernicious anemia was accomplished 
when Hoffman, in 1885, followed by Botkin, Reyher, and Rune- 
berg, showed that the presence in the intestine of many of these 
worms often leads to a severe or fatal anemia which may be made to 
disappear by the expulsion of the worms. While Reyher and Rune- 
berg, in 1886, and F. Miiller, in 1889, claimed that the morphology 
of the blood in these severe cases is identical with that of primary 
pernicious anemia, from the presence of megalocytes with increased 
Hb, megaloblasts, etc., the complete identity of the condition exist- 
ing in fatal cases with that of progressive pernicious anemia was 
fully established by Schaumann's extensive studies in the same 
locality. It is of great interest that in some of Schaumann\s cases, 
although the reduction of cells and Hb was not marked, yet Ehrlich's 
signs of progressiv^e anemia, megalocytes, with increased Hb and 
megaloblasts, were abundantly present. 



MISCELLAXJEO US PARASITIC DISEASES. 4,'J'J 

AVhile the fact that the worms cause the anemia seems to be proved 
bv the rapid recovery observed in some cases following their expul- 
sion (Wiltschur, Askanazy), no satisfactory explanation of the patho- 
genic action of the parasites has been obtained. It appears that 
large numbers of worms are required to produce the severe anemias, 
as many as 100 having been expelled from a patient of Boetticher, 
although in other instances the usual small number was found. The 
duration of the infection appears to exert little influence, as is evident 
from the cases reviewed by Askanazy. The writer secured four full- 
grown species from a healthy Swede who had been in America for 
seventeen years. Schapiro and Dehio, finding some dead parasites 
in their cases, concluded that only the decomposing worm produces the 
specific toxin which causes the anemia, but the majority of parasites 
found in severe cases are living. Wiltschur followed this clue fur- 
ther, finding that the majority of parasites were dead and decom- 
posing, or, as he concluded from alterations in the eggs, '^sick.'^ 
Some cases (Schaumann, Neubucher) in which anemia was present 
while no parasites, but only eggs, Avere found in the intestines at 
autopsy, Ehrlich believes can be explained as resulting from the 
complete absorption of recent decayed parasites. This reasoning it 
is difficult to follow, nor can great importance be attached to the 
results of Schaumann and Tallquist, who in the course of two weeks 
considerably reduced the red cells of a dog by injections of a glycerin 
extract of the crushed bodies of the worms. 

At present, therefore, it seems impossible to reach any satisfactory 
explanation why this parasite should behave at times as a harmless 
denizen of the intestinal tract, but at others should destroy its host 
through a fatal anemia. 

Changes in the Blood. In the great majority of Schaumann's 
cases the changes in the blood were characteristic of pernicious 
anemia. The red cells at first ranged from 2,150,000 to 395,000, 
an average of 1,290,000. They commonly exhibited marked changes 
in size; there was unusual excess of megalocytes with increased Hb, 
and these changes were sometimes present when the reduction in cells 
and Hb was not marked. 

A surprising improvement usually followed the expulsion of the 
worms, and most of the cases were discharged practically cured and 
apparently removed from danger of relapse. In some of Schaumann's 
cases, however, as in others reported by previous observers, the 
anemia progressed in spite of the expulsion of the worms. 

Nucleated red cells were present in all cases, and usually, but not 
always, the megaloblasts outnumbered the normoblasts. In Aska- 
nazy's cases normoblasts were found in small numbers among many 
megaloblasts, but the former rapidly replaced the latter as the anemia 
improved. Willson found many normoblasts in a case showing 
5,120,000 red cells and 60 per cent. Hb. Polychromasia and 
granular degeneration were pronounced at the height of the anemia, 
but diminished rapidly as the blood improved. The Hb was usually 
below 30 per cent., average at first 25 per cent., and the Hb-index 
was almost always normal or increased. 



478 



ANI3IAL PARASITES. 



The leucocytes were very seldom increased, and eosinophile cells, 
if present, did not attract the attention of Askanazy or any of the 
earlier observers, but were reported as increased in one of Schau- 
mann's cases. 

FILARIASIS. 

Several species of nematode worms inhabit the internal vessels and 
discharge their embryos into the circulation, giving rise to the con- 
dition known as filariasis. The embryos of the several species 
exhibit characters which should render possible their accurate iden- 
tification. 

According to Manson these features are principally (1) periodicity 
in the presence of the embryos in the peripheral blood. Filaria 
diurna appears during the day and disappears at night- Filaria 
nocturna appears at night only. Filaria 'perstans and Demarquaii 
are constantly present, both by day and by night. (2) The presence 

Fig. 42. 




Filaria nocturna, with stieath. (Lewis. 



or absence of a sheath which characterizes all species except Filaria 
perstans. (3) The character of the head and tail ends; the presence 
or absence of an armature; the blunt or pointed shape; the length of 
the tapering end. (4) Length, breadth, and general appearance of 
body. (5) Character of movements. Filaria noctura and diurna are 
lashing, but stationary. Filaria ^perstans lashing, but locomotor. 
The associated pathological condition, the nativity of the patient, and 
the character and location of the parent worm, if found, are also 
important. 

Filaria Nocturna. Developmental Cycle. The embryo is taken 
up from the blood of the host by the mosquito, in whose stomach it 
becomes rid of its sheath, and at the end of six to seven days develops 
in the viscera of the insect to a length of 1.58 mm., and acquires four 
lips and an alimentary canal. The farther stages between this form 
and the adult filaria of Bancroft have not been traced. The worm is 
next found in the lymphatics of the trunk and extremities, where it 
was first seen by Bancroft {F. Bancrofti). Here it measures 70 mm. 



MISCELLAXEOUS PARASITIC DISEASES. 479 

(males) to 94 mm. (females) in length, and looks like an animated 
white thread. Its movements are active and wriggling, the female 
tending to coil. The young filaria are discharged into the lymph, 
and, traversing the lobes, reach the blood stream. The reason of 
their exclusive appearance during the night is not known. 

Usually the presence of this worm and its embryos leads to no 
appreciable disturbance in the body of the host, and numerous cases 
have been discovered entirely by accident. In some cases chronic 
inflammation of the lymphatics results in a variety of pathological 
conditions, principally chyluria, lymphangitis, lymph scrotum, etc., 
and probably also to elephantiasis Arahum. 

The embryo of Filaria nodurna is a slender, snake-like worm, 
3 mm. by 0.0075 mm. in dimensions, with sharp-pointed tail tapering 
for about one-fifth the length of the body, and a blunt head. The head 
is composed of a six-lipped prepuce covering an extensive proboscis 
on which is a protrusible spine. The entire worm is enclosed in a 
delicate, hyaline, transparent sheath, which protrudes beyond head 
or tail, and within which the animal moves. This sheath exhibits 
fine cross-striations. The movements are actively lashing, writhing, 
coiling, and uncoiling, but with little or no tendency/ toward locomotion. 
The movements continue for several hours, or until the blood suffers 
drying. 

Occurrence in the Blood. The embryos begin to make their appear- 
ance in the blood from five to seven o'clock in the evening. The 
numbers increase for several hours during rest in bed, and after mid- 
night they Lisually become less abundant, disappearing at seven or eight 
in the morning, but an occasional specimen may sometimes be found 
at any time in the day. This remarkable periodicity depends on the 
habits of the host, since it becomes transposed when the subjects sleep 
in the daytime, and it is considerably disturbed by irregular habits and 
by fever. It is also adapted to the nocturnal habits of the mosquito. 
The numbers of filaria to be found in the blood depend upon the time 
of the examination and upon the number of parent worms, but for 
the same patients they are usually quite uniform. From ten to fifty 
may be found under one cover-glass specimen, but they are often 
much less abundant. Several hours' search through thick blood 
smears may be required for the demonstration of a single filaria 
embryo, in cases in which they are present, though very scarce. It 
is sometimes to be observed that the results of the blood examination 
are negative as long as the patient is going about, although a 
moderate number of embryos are found after the patient has been 
in bed a few days. 

Changes in the red cells referable to the presence of filaria embryos 
are not usually demonstrable. Even when present in enormous 
numbers and for many years the parasites exert no deleterious action 
on the blood, and anemia, when present, must be referable to 
secondary causes. 

Calvert examined the blood at hourly intervals for twenty-four 
hours in two cases of filariasis, finding leucocytosis, reaching 26,666 
and 14,000. The eosinophile cells varied from 8 to 22 per cent, in 



480 



ANIMAL PARASITES. 



one case and from 3 to 20.5 per cent, in the other. The leucocy- 
tosis and excess of eosinophile cells were most marked during the 
daytime, when the embryos in the peripheral circulation were scanty. 
He thinks that eosinophilia diminishes as the infection becomes 
chronic. 

Method of Demonstration. On account of the large size and active 
movements of the filaria, examination of the fresh blood may be 
recommended in the search for the parasite when its presence is sus- 
pected. Fresh specimens prepared in rather thick layers should be 
looked over with a moderately low-power lens. Permanent speci- 
mens may be secured by smearing the blood on glass slides, fixing 
by heat or alcohol, and staining by methylene blue. Canada balsam 
causes fading after a year or more, and Manson uses glycerin jelly 
as a mounting medium. 

Filaria Diurna. In four cases of filariasis occurring in negroes on 
the coast of Africa, Manson observed filaria resembling Filaria noc- 
turna in the blood only between 8 a.m. and 9 p.m. He suggests 
that the Filaria loa is the parent form, since one of his cases had pre- 
viously suffered from this parasite, and that the '' mangrove fly" is 
the intermediate host. 

Filaria Perstans. In some portions of the west coast of Africa 
Manson found that two-thirds of the natives are infected with a 
special form of filaria. The embryos are thinner and longer than 
Filaria nodurna, 23 mm. by 0.0045 mm. ; they lack a sheath, execute 
movements, often very rapid, of locomotioii, occur in much smaller 
numbers in the blood, and are found both by day and by night. 

TRYPANOSOMIASIS. 



Although infection of the blood by various forms of trypanosomes 
has long been recognized in several tropical diseases of domestic 




Trypanosoma gambiense in human blood. (After Dutton.) 

animals as surra, nagana, " mal de caderas," etc., the occurrence 
of pure infections by a form of this parasite in the blood of man has^ 



MISCELLANEOUS PARASITIC DISEASES. 481 

only been satisfactorily demonstrated within the past year, 1902-03, 
when no less than eleven authentic cases have been reported by 
Dutton, Forde, and Macson.^ Nepveu, however, reported in 1898 
the discovery in the blood of six malarial patients of bodies having 
all the characters of trypanosomes. 

In man the disease follows a chronic course with intermittent 
fever, marked erythema multij'orme of trunk and limbs, edema of 
eyelids and ankles, emaciation, and enlargement of the spleen. 

Morphology and Occurrence of the Parasite. In stained 
preparations the parasite and its flagellum measured in Datton's 
case l^fi to 2b (I in length and 2// to 2.8// in width. The posterior 
end of the wormlike body is blunt and conical, while the anterior 
end is pointed. An oval nucleus consisting of chromatin grains 
occupies a central position, while in the posterior end lies a centro- 
some or micronucleus giving origin to the flagellum which curves 
forward along the free border of the undulatitig membrane of the 
parasite and projects some distance beyond the anterior end of the 
body. By Romanowsky's method these structures stain like those 
of the malarial organism. The undulating membrane is an achro- 
matic structure whose free border is continuous with the flagellum 
while the attached border begins at the centrosome and ruus forward 
to the pointed end of the body. The web is transparent. The 
parasite exhibits slow spiral movements of progression. They are 
never found in the red cells, but may be englobed and destroyed by 
the leucocytes. Multiplication has been observed in experimental 
infections in rats, and occurs by transverse and longitudinal division 
and by segmentation (Rabinowitsch and Kempner, Francis). In- 
fection in man is probably carried by mosquitoes (Dutton) and in 
rats by fleas, lice, and by the food. 

The number of parasites seen in the blood is scanty, not more 
than three to eight being found under a three-quarter inch cover- 
glass, while during apyrexia they were not found at all. Repeated 
examinations may be required for their detection. 

The Hb and red cells are moderately reduced, the leucocytes 
slightly increased, with relative lymphocytosis. In Button's case 
the following results are reported: Hemoglobin, 76 per cent.; 
red cells, 3,850,000 ; leucocytes, 12,000, of which 60 per cent, 
were mononuclear, 40 per cent, polynuclear. 

SPOTTED FEVER OF MONTANA. 

According to the observations of Wilson and Chowning this pecu- 
liar local disease is referable to infection of the red blood cells by an 
hematozoon resembling the parasite of Texas cattle fever. 

Bibliography. 

Miscellaneous Parasitic Diseases. 

Ashford. N. Y. Med. Jour., vol. Ixxi. p. 552. 
Askanazy. Zeit. f. klin. Med., Bd. 27, p. 492. 
Atkinson. Philadelphia Med. Jour., vol. iii. p. 1243 

31 



482 ANIMAL PARASITES. 

Blumer, Neuman. Amer. Jour. Med, Sci., vol. cxix. p. 14. 

Boetticher. Cited by Askanazy. 

Bohland. Miinch. med. Woch., 1894, p. 901. 

Botkin. Cited by Schaumann. 

Brown. Johns Hopkins Bull., 1897. Jour. Exper. Med., 1898, p. 315. 

Bucklers. Miinch. med. Woch., 1894, p. 22. 

Cabot. Boston Med. Surg. Jour., vol. cxxxvii. p. 676. 

Calvert. Johns Hopkins Bull., vol. xiii. p. 133. 

Cinisella. Annali univ. de Med., 1878. 

Dehio. St. Petersburg med. Woch., 1891, No. 1. 

Demme. Ber., Jenner Kinderspital. Bern., 1890, p. 31. Cited by Grawitz. 

Dutton. Thompson- Yates Lab. Rep., Part II., vol. iv. p. 455. Brit. Med. 
Jour., 1903, i. p. 304. 

Forde. Jour. Trop. Med., 1902., No. 17. 

Francis. U. S. Hvgienic Lab. Bull., No. 11. 

Grassi. Archiv. p. 1. sci. Med., 1879, No. 20. Annah univ. di Med., 1878. 

Griesinger. Archiv f. phvs. Heilk., 1854, p. 554. 

Gwyn. Cent. f. Bact., Bd. 25, p. 746. 

Heisse. Casper's Vierteljahrsschrift, Bd. 8. 

KartuUs. Virchow's Archiv, Bd. 152, p. 471. 

Kerr. Philadelphia Med. Jour., vol. vi. p. 346. 

Lambert, Brooks. Trans. N. Y. Path. Soc, 1900, p. 167. 

Leichtenstern. ^Wien. klin. Rundschau, 1898. ^Deut. med. Woch., 1887-88. 

Lortet, Vialleton. Etude s. 1. Bilharz. hematob., Paris, 1894. 

Lussana. Ri vista clin., 1890, No. 4, p. 750. 

Manson. Allbutt's Syst. of Med., vol. ii. ^Brit. Med. Jour., 1903, vol. i. pp. 
720, 765, 1249. 

Menche. Cent. f. klin. Med., 1882, p. 161. 

Midler, Rieder. Deut. Archiv klin. Med., Bd. 48, p. 26. 

Nepveu. Mem. Soc. de Biol., December 24, 1898. 

Neubucher. Inaug. Diss. Konigsberg, 1898. 

Perroncito. Archiv. p. 1. sci. Med., 1881, No. 2. Compt. Rend. Acad. Sci. 
1882, No. 1. 

Reijher. Deut. Arch. klin. Med., Bd. 39, p. 31. 

Rabinowitsch, Kempner. Zeit. f. Hvg., Bd. 30, p. 251. 

Sandwith. Brit. Med. Jour., 1894,'l., p. 1362. 

Schapiro. Zeit. f. klin. Med., Bd. 13. 

Schauman. Zur Kenntniss d. Bothrioceph. Anaemic, 1894. 

Schaunian, Tallquist. Deut. med. Woch., 1898, No. 20. 

V. Schopf. Wien. med. Zeitung, 1888, Nos. 46-48. 

Solley. Presby. Hosp. Rep., vol. v. p. 188. 

Sondereger. Correspond., Schweizer Aerzte, 1880. 

Stump. Philadelphia Med. Jour., vol. iii. p. 1318. 

Teissier. Compt. Rend. Acad. Sci., T. 121, p. 171. 

Thayer. Philadelphia Med. Jour., vol. i. p. 654. 

Willson. Amer. Jour. Med. Sci., vol. cxxiv. p. 262. 

Wilson, Chowning. Jour. Amer, Med. Assoc, 1902, vol. xxxix. p. 131. 

Wiltschur. Deut. med. Woch., 1893, p. 715. 

Wucherer. Deut. Archiv klin. Med., 1872. 

Zappert. ^ Wien. klin. Woch., 1892, No. 24. ^ Zeit. f . klin. Med., Bd. 23. 

Zinn, Jacoby. Berl. klin. Woch., 1896, No. 36. 



APPENDIX. 



During the passage of this volume through the press contributions 
appearing in certain lines call for the additional paragraphs appended.. 

Dare's Alkalimeter. 

Dare {Philadelphia Medical Journal, vol. xi. p. 137) has devised 
a commendable method and apparatus for the clinical estimation of 
the alkalinity of blood. Its principal features are the avoidance of 
a foreign indicator, the point of neutralization by tartaric acid being 
determined by the disappearance of the spectroscopic absorption 
bands of oxyhemoglobin, the use of an automatic 20 c.mm. blood 
pipette, and the absence of undue exposure to air of the manipu- 
lated blood. 

Further Observations on Polychromasia and Granular 
Degeneration of Red Cells. 

The observations on polychromasia and granular degeneration of red 
cells seem to indicate a certain relation of these processes to each other 
and to developmental anomalies in the erythrocyte. While present 
knowledge hardly warrants positive conclusions, one will probably 
not be greatly in error who conceives of them all as the expressions of 
one series of changes. It would appear that the imperfectly devel- 
oped red cell may be deficient in Hb, or may contain imperfectly 
oxidized Hb (Sherrington), which give it the character of the 
polychromasia of Maragliano ; or that a portion of the cell may be 
entirely free from Hb (polychromasia of Gabritschewsky) ; or the 
imperfectly developed red cell, while deficient in Hb, may show a 
clumping of its nuclear constituent in the form of fine basic granules 
(granular degeneration), while the irregular diffusion of nuclear 
elements in the megaloblast occasionally yields large and small baso- 
phile granules in the cytoplasm interpreted by some as an evidence of 
karyorrhexis. That all of these changes frequently occur in imper- 
fectly developed cells is beyond question, w^hile the belief that red 
cells once perfectly formed may suffer such alterations seems much 
less certain. The writer is inclined to look upon all these changes 
not as occurring in the circulation, but as the result of disturbances 
of the function of red-cell formation in the marrow. 

The results of Schmidt^s experiments {Expcr. Bcltr. z. Path. d. 
Blutes, Jena, 1902), showing that after the intravenous injection of 



484 APPENDIX. 

lead salts granular degeneration does not occur in the red cells of the 
ligated ear, strongly support this view and indicate that these gran- 
ules are nuclear particles representing an anomaly of development. 

Leukanemia. 

This is a term suggested by v. Leube to indicate certain cases of 
rapidly fatal anemia in which the blood shows pronounced characters 
of pernicious anemia, the moderate leucocytosis of acute lymphemia 
or myelemia, while the viscera exhibit distinct leukemic lesions. 
In this group fall the majority of cases of acute leukemia, cases of 
pernicious anemia described as terminating in leukemia, cases of 
lymphatic leukemia without lesions in the lymph nodes, and pos- 
sibly some cases of v. Jaksch's anemia. The typical case is charac- 
terized by peracute or subacute course, fever, gingivitis, and hemor- 
rhages. The blood first shows the changes of pernicious anemia, 
with slight or no leucocytosis. Later there is moderate or pro- 
nounced increase of large lymphocytes or myelocytes. Eosinophile 
cells are absent or scanty. There are moderate hyperplasia of lymph 
nodes and spleen, extreme diffusion of red marrow, and leukemic 
deposits in the liver. Siderosis of the liver and Charcot-Leyden 
crystals are absent. It is believed that the condition results from 
the action of a toxic or infectious agent upon the progenitors of the 
red and white cells. The possibility that the progenitors of the red 
and white cells constitute a single cell type in the adult marrow, 
and the striking clinical characteristics of these cases, are at least a 
partial warrant for the general introduction of this term. Leukanemia 
is, then, a term referring to a disease which may be regarded provi- 
sionally as constituting a point of union of leukemia and pernicious 
anemia. 

V. Leuhe. Deut. Klinik, 1902, Lief. 42. Miinch. med. Woch., 1900, p. 1121. 

Luce. Deutsch. Arch, f, klin. Med., Bd. lxx^'ii. p. 215. 

Arneth. Ibid., Bd. Ixix. p. 331. 

Kormoczi. Deut. med. Woch., 1899, pp. 238, 775. 

Hitschman, Lehndorff. Zeit. f. Heilk., 1903, p. 190. 

Serumtherapy in Anemia. 

Bielonovsky reports very striking improvement of the blood in 
nine cases of primary pernicious and severe secondary anemia by 
injections of 5 c.c. to 10 c.c. of hemolytic serum prepared in the rabbit. 

Bielonovsky, These de Doctorat, ref. in Bull. Instit. Pasteur, 1903, p. 126. 

Bacteriological Study of the Blood in Scarlet Fever. 

Hektoen reports the isolation of streptococci from the circulating 
blood of 12 of 100 cases of scarlet fever, most frequently in severest 
cases. In two cases of the series pure cultures of staphylococcus 



APPENDIX. 485 

aureus were obtained, and in one case bacillus typhosus. Weaver 
and Ruediger find that neither normal nor scarlatinal blood serum 
has any bacteriolytic action on various strains of streptococci. 

Hektoen. Journ. Amer. Med. Assoc, March 14, 1903. 
Weaver, Riiediger. Medicine, July, 1903. 

Bacteriology of the Blood in Pneumonia. 

The following additional studies of the blood from the basilic vein 
in pneumonia favor the conclusion that this disease is in the great 
majority of cases a form of bacteremia. 

Casati demonstrated the pneumococcus in the blood of 25 consecu- 
tive cases by inoculation in mice. Positive cultures are reported in 
all of 8 cases by Berghini, in 55 of 57 cases by Baduel, and in 74 of 
83 cases by Rosenow. The last observer finds it possible to iden- 
tify the pneumococcus in smears of the blood in many cases. 

Casati. Jahresbr. f. Path,, 1893. 

Berghini. La Chn. med. Ital., 1899, No. 5. 

Baduel. La Rif. Med., xv. p. 170. 

Rosenow. Trans. Chicago Path. Soc, 1903, p. 265. 

Sleeping-sickness. 

Castellaini and Bruce report the discovery of trypanosomes in the 
aspirated cerebrospinal fluid of all of 38 cases^ and in the blood of 
12 of 13 cases examined. They believe this infection to be the cause 
of the disease, while the streptococcus is a frequent secondary infecting 
agent. This trypanosome differs slightly from that described by 
Dutton. 

Castellaini, Bruce. Brit. Med. Jour, 1903, vol. i. pp. 1218, 1431. Jour. Trop. 
Med., 1903, p. 167. 



INDEX. 



ABSCESS, 326 
of liver. 392 
Absorption, effects on blood, 402 
Acetonemia, 83 

Acidemia in carcinoma, 91, 426 
Acidity of blood, 92 
Actinomycosis, 335 
Addison's disease, 375 
Agglutinins, 145 
Albumins of serum, 75 
Albumose, occurrence in blood, 77 
.llexines, 128, 140, 144, 158 
Alkalescence of blood, Engel's alkali- 
meter, 60 
estimation of, 59 
Dare's method, 483 
Limbeck's method, 61 
Lowy's method, 59 
Schultz-Schultzenstein's 

method, 60 
Wright's method, 61 
in carcinoma, 91, 426 
in cholera, 404 
in diabetes, 374 
in fever, 91, 92, 279 
general factors in, 90 
in gout, 377 
in hemoglobinemia, 369 
in leukemia, 247 
in uremia, 418 
Amboceptor, 144, 158 
Anadenia, 209 

Analyses of blood, interpretation of, 17 
Ankylostoma duodenale, 474 
anemia from, 206, 475 
Anemia, from Bothriocephalus latus, 
206 
changes in blood, 220, 476 
infantum pseudoleukemica, 268 
"" pathological anatomy, 271 
lymphatic, 171, 344 
progressive pernicious, 202 

changes in blood in, 216 
chemistry, 216 
Hb, 217 
leucocvtes, 221 
red ceils, 218 
etiology, general, 204 

special, 206 
gastro-intestinal diseases 

in, 208 
hemorrhages as a cause of, 
207, 355, 394, 398, 475 



Anemia, progressive pernicious, histor- 
ical, 202 
malaria as a cause of, 208 
marrow lesions in, 212 
nervous system in, 211 
pathogenesis of, 215 
after pregnancy, 207 
resume of chief facts, 222 
scope of term, 205 
typhoid fever as a cause 
of, 208 
secondary, eosinophiles in, 162 

origin of, 117 
of V. Jaksch, 268 

significance of, 270, 484 
splenic, 264 
Anesthesia, 110 
Anguillula stercoralis, 473 
Anhydremia, 17 
Anisocytosis, 97 
Anthrax, 335 
Antialbumid, 73 
Antifebrin poisoning, 366 
Antipyrin poisoning, 366 
Antitoxin in diphtheria, effects on 

blood, 292 
Antitoxins, etc., 145 
Appendicitis, 325 

Arsenic, effect on red cells, 113, 363 
Arseniuretted hydrogen, poisoning by, 

363 
Ascaris, 206, 473 
Ascites, 394 

Ash of blood, inorganic principles, 78 
Asphyxia, 408 
Asthma, 409 

eosinophilia in, 162, 409 



BACTERIA, action of, on blood, 279 
in blood of pneumonia, 289, 485 
in cholera, 404 
in chorea, 386 
in endocarditis, 413 
in influenza, 333 
in leprosy, 350 
in leukemia, 232 

method of examining blood for, 67 
in purpura hemorrhagica, 354 
in rheumatism, 328 
in scarlet fe^•er, 300, 484 
in scurvy, 358 
in septic processes, 323 



488 



INDEX. 



Bacteria in tuberculosis, 348 

in typhoid fever, 306 
Bactericidal action of blood, 139 
Banti's disease, 265 
Barlow's disease, 359 
Basedow's disease, 387 
Basic capacity of blood, 92 
Basophilia, perinuclear, Neusser's, 132 
Baths, cold, in typhoid fever, 304 
Beriberi, 386 
Bibliography, carcinoma, sarcoma, 428 

chemistry, 93 

chlorosis, 200 

constitutional diseases, 382 

development of blood cells, 188 

diphtheria, 308 

eosinophilia, 173 

exanthems, 308 

fever, 280 

general physiologv, 68 

heart, 418" 

hemopoietic system, 405 

hemorrhagic diseases, 369 

infectious diseases, 336 

V, Jaksch's anemia, 272 

kidneys, 418 

lepros}^, 350 

leucocytes, leucocytosis, 158 

leukemia, 251 

lungs, 418 

lymphoc3^tosis, 173 

malaria, 464 

morphology and physiology, 120 

nervous and mental diseases, 387 

parasitic diseases, 481 

pernicious anemia, 224 

pneumonia, 308 

pseudoleukemia, 266 

relapsing fever, 469 

splenectomy, 276 

syphihs, 350 

tuberculosis, 350 

tvphoid fever, 308 

Widal's test, 319 
Bile, detection of, 84 

effects of, on blood, 389 
Bilharzia hematobia, 472 
Blackwater fever, 367 
Blood crises, 195, 220, 222, 321 

dust, 133 

islands, 175, 213, 

plates, chemistry of, 74 
development of, 186 

smears, fixation of, 54 
Bones, tuberculosis of, 348 
Bothriocephalus latus, 476 

anemia from, 206, 220, 476 
Breast, carcinoma of, 425 
Bremer's reaction, 64 
Bronchitis, 410 
Burns, 362 



CARBONIC dioxide, occurrence in 
blood, 90 i 

Carbonic oxide Hb, chemistry of, 72 | 



Carbonic oxide Hb, spectrum of, 30 

poisoning, 366 
Carcinoma, 421 

acidemia in, 91, 426 

alkalescence in, 426 

of esophagus, 394 

of breast, 425 

of Uver, 391 

special factors in anemia of, 423 

specific gravity in, 426 

of stomach, 399, 209 

digestion leucocytosis in, 401 
Centrosomes, 127 
Charcot-Levden crystals in leukemia, 

248 
Chemistry of blood, 71 

in diabetes, 373 

in gout, 376 

in leukemia, 247 

in nwxedema, 381 

in nephritis, 416 

in osteomalacia, 377 

in pernicious anemia, 216 

in pneumonia, 283 

in rachitis, 380 

in septic processes, 322 

in tuberculosis, 348 

in uremia, 417 
Chemotaxis, 134 
Children, vide Infants. 
Chlorosis, 191 

chemistry, 196 

Egyptian,' 474 

eosinophiles in, 162 

etiology, 191 

Hb, 194 

iron in, 112, 193, 197 

leucocytes, 198 

marrow in, 196 

nervous system in, 192 

nucleated red cells, 195 

pseudo-, 199 

red cells of, 194 

regeneration of blood, 197 

specific gravitv, 193 

thyroid, 387 

varieties of, 198 
Cholelithiasis, 392 
Cholemia, occurrence and detection of, 

83 
Cholera, 403 

alkalescence in, 404 

bacteria in, 405 

infantum, Ij'-mphocytosis of, 397 
Chorea, 386 

bacteria in, 386 
Chromic acid poisoning, 365 
Cirrhosis of liver, 392, 393 
Coagulability, determination of, 61 

in hemoglobinemia, 369 
Coagulation, in blood of fever, 280 
Cold, effect in concentrating blood, 19, 

109 304 
Colitis, 403 
Coma, in cancer, 426 

in diabetes, 373, 374 



INDEX. 



489 



Coma in malaria, 456 
in uremia, 417 

Complement, 139, 144, 158 

Concentration of blood, effect of cold on, 
19 
of electricity on, 19 
of massage on, 19 

Conjugation of malarial parasites, 454 

Constitutio lymphatica, 170, 191 

Constitutional diseases, 353, 372 

Con^Tilsions, 385 

Crioscopy, 62 

Cytases,'l40, 144 



DARE'S alkalimeter, 483 
hemoglobinometer, 51 
Defibrinated blood, transfusion of, 364 
Depletion, effects of, on blood, 402 
Dementia, 384 

Development of blood cells, 175 
Diabetes, 372 

alkalescence in, 374 

Bremer's reaction in blood of, 64 

chemistry of, 373 

glycogen in, 374 

jecorin in, 374 
Diarrhea, 403 
Diarrheal diseases, polycythemia of, 

109, 403, 409 
Diastatic ferment, 87 
Digestion, effect on red cells, 105 

leucocytosis, 146, 401 
Diphtheria, 290 

antitoxin in, effects of, on blood, 
292 

degeneration of leucocytes in, 292 

lymphocytosis in, 291 
Distoma hematohium, 472 
Dry specimens, 53 
Duodenal ulcer, 402 
Dysentery, 403 
Dyspepsia, 397 



ECHINOCqCCUS, in liver, 393, 165 
Electricity, effect in concentrat- 
ing blood, 19 
Emphysema, 410 
Empyema, complicating pneumonia, 

284 
Endocarditis, 410 

bacteria in, 413 

gonorrheal, 413 

malignant, 412 

polycythemia of, 109, 411 
Endometritis with sepsis, 321 
Eosinophilia, 161 

in ankylostomiasis, 165, 474 

with ascarides, etc., 473 

in asthma, 162, 409 

in diagnosis, 167 

in leukemia, 162, 243 

marrow changes in, 166 

origin and significance of, 166 

in pneumonia, 286 



Eosinophilia, post-febrile, 164 

in rachitis, 380 

relation to lymphocytosis, 172 

in sarcoma, 163, 428 

in scarlet fever, 164, 299 

in trichinosis, 165, 470 
Eosinophile cells, chemistry of, 186 

development of, 166, 185 

estimation of, 42 

proportions, 161 

structure, 125 
Epilepsy, 384 

Ivmphocvtosis in, 385 
Erj^sipelas, 324, 326 
Esophagus, lesions of, 394 
Ether, 110 
Exanthemata, 294 

eosinophiles in, 164 

FAT, demonstration of, 67 
occurrence and estimation of, 83 
Ferments, 86, 139 
Ferrometer, Jolles', 52 
Fever, alkalescence in, 91, 92, 279 

blood in, 164, 277 

hemocytolysis in, 277 
Filariasis, 478 

Fixation of blood smears, 54 
Flagellate bodies, preparation of, 431 
Fleischl's hemoglobinometer, 45 



GASTRITIS, 396 
Gastro-intestinal diseases, 394 

and pernicious anemia, 
208 
of infants, 397 
Glanders, 335 

Glucose,occurrence and estimation of,81 
Glycogen, demonstration of, 66 

in diabetes, 374 

in leukemia, 248 

occurrence, 81, 248, 323, 326, 374 

in pneumonia, 288 
Glycolytic ferment, 81, 87, 374 
Goldhorn's stain, 435 
Granules, EhrHch's, 126, 128 
Gonorrhea, 331 

eosinophiles in, 165 
Gout, 376 

alkalescence in, 377 

chemistry of, 376 

eosinophiles in, 165, 376 

uric acid in blood of, 377 
Gowers' hemoglobinometer, 43 
Graves' disease, 387 
Guaiac test, 24 
Guaiacol, poisoning b}^, 364 



HB, hemoglobin, 29 
chemistry of, 71 
estimation of, 43 
spectrum of, 29 
Heart, congenital disease of, 414 



490 



INDEX. 



Heart, diseases of, 410 
Hemameba immaculata, 444, 449 
Hematin, chemistry of, 73 

spectrum of, 29 
Hematoblasts, 177 
Hematocrit, 31 
Hematocytometer, 35 

Oliver's, 40 

Thoma's 35 

directions for using, 37 
sources of error, 39 
Hematoidin, chemistry of, 73 

in globulicidal serum, 76 
Hemin test, 24 
Hemocytolysis, 118, 359, 426 

in fever, 277 
Hemoglobinemia, 72, 221 

alkalescence in, 369 

coagulabilit}' in, 369 

malarial, 367 
Hemoglobinometer, 43 

Dare's, 51 

Fleischl's, 45 

Gowers', 43 

Haldane's, 44 

Miescher's, 47 

Oliver's, 48 

Tallquist's, 44 
Hemoglobinuria, 366 
Hemokonia, 133 
Hemolymph nodes, 183 
Hemolysins, 144 
Hemophilia, 356 

Hemorrhage, a cause of pernicious ane- 
mia, 207, 394, 398, 475 

changes in blood from, 114 
Hemorrhagic diseases, 353 
Hemosiderin, chemistry of, 73 
Histon, chemistry of, 74 
Hunger, blood in, 396 
H5rdremia, febrile, 278, 410 
Hydrobilirubin, 79 
Hydrocyanic acid poisoning, 366 
Hyperacidity, gastric, 396 
Hypochondriasis, 387 
Hypoleucocytosis, experimental, 136 

in pneumonia, 286 

in septicemia, 322 
Hysteria, 387 



IMMUNE body, 139, 144 
Immunity, 138 

Ehrlich's theories of, 141 
Infants, atrophy of, 264, 395, 397 
characteristics of blood, 270 
cholera infantum, 397 
digestion leucocj^tosis, 147 
eosinophiles in blood, 161 
hemorrhage, effects of, 116 
leucocytes, fetal, 184 

proportions of, 129, 161, 170 
leucocytosis of newborn, 149 
leukemia, occurrence of, 230 
liver, formation of red cells in, 180, 
270, 389 



Infants, lymphocytes in, 170, 171 
lymphocvtosis of infectious dis- 
" eases, 171, 287, 291 
marasmus, 264, 395, 397 
marrow, limits of red, 180 
megaloblasts, occurrence of, 98 
melena neonatorum, 343, 355 
normoblasts, occurrence, 98 
pernicious anemia in, 206, 207 
polychromasia in fetal red cells, 101 
pseudoleukemia in, 258 
purpura hemorrhagica in, 354 
red cells, numbers, 107 

size, 97 
spleen in anemia, 180 
splenomegal}^, 264 

Influenza, 332 

bacteria in, 333 

Inorganic principles of blood, estima- 
tion of, 80 

Interpretation of analj^ses of blood, 17 

Intestinal intoxication in leukemia, 231 

Intestine, diseases of, 402 

Iron in blood, estimation of, 52 
in chlorosis, 112, 193, 197 
effect of, on red cells. 111 
indications for, 112 
occurrence of, 79 

Isolysis, 361 



JAKSCH, v., anemia, relation to 
pseudoleukemia, 268 
Jaundice, 390 

polycythemia in, 391 
Jecorin, in diabetes, 374 
Jenner's stain, 56 
Jolles' ferrometer, 52 
Justus' test, 341 



K 



IDNEY, diseases of, 414 
Kreatinin, 418 



LEAD, effects on blood, 113 
Leprosy, 349 

bacteria in, 350 
serum diagnosis of, 350 
Leucocidins, 362 

Leucocytes, acute degeneration, 130 
chemistr}^ of, 73 
chronic degeneration, 131 
classification, 123, 126 
degeneration of, in diphtheria, 292 

in pneumonia, 288 
degenerative changes in, 130, 242 
development of, 180, 166 

of ^'arieties, 184 
diminution of neutrophile granules, 

131, 242 
estimation of, 41 

in same preparation with red 
cells, 42 
fatty degeneration, 132 
finer structure, 127 



INDEX. 



491 



Leucocytes, fragmentation of bodies, 
131 

hydropic degeneration, 132, 242 

morphology, 123 

neutrophile, development of, 184 
structure, 124 

nuclear changes, 131, 242 

numbers, 128 

in pathological blood, 125 

pigmented, in malaria, 463 

polvnuclear, degenerative changes 
ill, 131, 242 

proportions of forms, 129 

''shadows," 131, 288, 291 
Leucocytosis, antemortem, 154 
in leukemia, 246 

cachectic, 152 

changes in marrow, 135 

classification, 133 

clinical types, 146 

course of, 136 

digestion, 146, 401 

experimental, 155 

in malaria, 462 

in newborn infants, 149 

in phthisis, 346 

post-hemorrhagic, 151 

in pregnancy, 148 

relation to immunity, 138 

significance of inflammatory, 133 
Leukanemia, 484 
Leukemia, 227 

acute, 241, 245, 484 

alkalescence in, 247 

bacteriology, 232 

changes in blood, 239 
leucocvtes, 241 
red ceils, 240 
in viscera, 233 

Charcot-Leyden crystals in, 248 

chemistry, 247 

diagnosis, 249 

eosinophiles in, 162 

etiology, 230 

extirpation of spleen in, 275 

glycogen in, 248 

history, 227 

intestinal intoxication in, 231 

leucocytosis, antemortem, in, 246 

lymphatic, 244 

lymphocytes in, 243 

malaria as a cause of, 231 

marrow in, 234 

mast-cells in, 244 

nucleins in, 248 

pathogenesis, 237 

peptone in, 248 

protozoa in, 233 

rachitis as a cause of, 231 

relation to pseudoleukemia, 258 

resemblance to a neoplasm, 239 

septicemia in, 246 

specific gravity in, 247 

spermin in, 246 

stomatitis as a cause of, 231 

syphilis as a cause of, 231 



Leukemia, transformation into perni- 
cious anemia, 247 

transformations of type, 247 

tuberculin in, 246 

types of myelocytes in, 241 

tyrosin in, 248 

uric acid in, 248 

variations in blood changes, 245 

xanthin bodies in, 248 
Lipacidemia, 83 
Lipemia, 83, 374 
Liver, 389 

abscess of, 392 

acute 5^ellow atrophy of, 393 

cancer of, 391 

diseases of, eosinophiles in, 162, 393 

echinococcus cyst of, 393 

embryonal, nucleated red cells in, 
179 

hypertrophic cirrhosis, 392 
Lungs, diseases of, 407 
asphyxia, 408 
bronchitis, 410 
emphysema, 409 
eosinophiles in, 162, 409 
Lutein, 79 
Lymphatic anemia, 171 

leukemia, transformation into m3^e- 
lemia, 235, 484 
marrow in, 234 
Ljmiphocytes, development of, 184 

large, in pneumonia, 287 

in leukemia, 243 

degenerative changes in, 244 
large, 244 

peculiar, in pneumonia, 288 

proportions, 129 

relation to neutrophile cells, 238 

structure, 123 
Lymphocytosis, antemortem, 154 

in cholera infantum, 397 

in congenital svphilis, 171, 342 

in diphtheria, 171, 291 

in epilepsy, 385 

experimental, 172 

large cells in, 172 

in malaria, 462 

occurrence of, 169 

origin of, 169 

in rachitis, 170, 380 

relation to eosinophilia, 172 

in sarcoma, 170, 427 

in typhoid fever, 170, 305 
Lymphoma, 255 
Lymphosarcoma in pseudoleukemia, 256 



"\/rALARIA, 431 



anemia of, 459 

pathogenesis of, 461 
a cause of leukemia, 231 

pernicious anemia, 208 
chronic, 457, 459, 463 
coma in, 456 
conjugation, 454 
crescentic bodies, 450 



492 



INDEX. 



Malaria, development of parasite in 
mosquito, 453 

without diminution of red cells, 457 

eosinophiles in, 164, 463 

estivo-autumnal parasite, 443 

extirpation of spleen in, 275 

flagellate bodies, 432, 451 

hemameba immaculata, 444, 449 

hemoglobinemia, 367 

leucocytosis of, 462 

Ij'mphocytosis in, 462 

nucleus and chromatin of parasites, 
436, 439, 440, 446 

occurrence of parasites in blood, 
455 

without parasites in blood, 457 

phagocytosis in, 463 

pigment, estivo-autumnal, 446 

pigmented leucocytes, 463 

quartan parasite, 442 

quinine, action of, 458 

quotidian parasite, 446 

red cells in, 460 

remittent, 457 

rings, comparison of tertian and es- 
tivo-autumnal, 437 
estivo-autumnal signet, 443 
significance of, 436 
tertian, 435 

rosettes, estivo-autumnal, 445 
quartan, 443 
tertian, 441 

species, plurality of, 446 

splenectomy in, 275 

technics, 431 

tertian parasites, 435, 447 

tvphoid fever and, 458 
Malta"^ fever, 334 
Mania, 384 

Marrow, extrusion of nuclei of red cells 
in, 178 

giant cells in, 177 
in chlorosis, 193 

lesions in pernicious anemia, 212 

in leukemia, 234 

in lymphemia, 234 

malarial parasites in, 460 

normal limits of red, 180 
Massage, effect in concentrating blood, 

19 
Mast-cells, development of, 184 

in leukemia, 244 

occurrence of, 167 

proportions, 129 

staining of, 57 

structure, 125 
Measles, 3.00 

German, 301 

protozoa in, 296, 300 
Megaloblasts, structure, significance, 99 
Megalocvtes, occurrence, significance, 

98, 361 
Melancholia, 384 
Melanin, chemistry of, 73 
Melena neonatorum, syphilitic, 342 
Meningitis, tuberculous, 347 



Menstruation, red cells in, 105 

Mental diseases, 384 

Mercur}^, effects on blood in syphilis, 339 

on red cells, 113 
Methemoglobin, chemistry of, 72 

spectrum of, 30 
Methemoglobinemia, 364 
Microcytes, occurrence, significance, 97, 

219, 361 
Miescher's hemoglobinometer, 47 
Mosquito, development of malarial para- 
site in, 453 
Mucinemia in myxedema, 381 
Muscular exertion, leucocytosis in, 148 
Myeloblast, 124 
Myelocytes in congenital syphilis, 342 

degenerative changes in, 242 

morphology, 125 

occurrence of, 168 

in pneumonia, 288 

tvpes of, in leukemia, 241 
Myxedema, 380 

chemistry of, 381 

mucinemia in, 381 

thyroid therapy in, 381 



NAGANA, 480 
Nephritis, 415 

chemistry of blood in, 416 
eosinophiles in, 163 
Nervous diseases, 384 

eosinophiles in, 163, 385 
influences, effect on qualitv of 
blood, 18 
system in chlorosis, 192 

in pernicious anemia, 211 
Neurasthenia, 387 
Nitrites, poisoning by, 365 
Nitrobenzol poisoning, 365 
Nocht-Romanowsky method, 434 
Normoblasts, occurrence, significance, 

98 
Nucleated red cells, 98 

transformation into disks, 178 
Nuclein, chemistry of, 74 
Nucleins in leukemia, 248 
Numbers of blood cells, 35 



OBESITY, 374 
Oligocythemia, 114 
Oiigoplasmia in cholera, 405 

in chlorosis, 199 
Oliver's hemoglobinometer, 48 
Operations, surgical, effects on blood, 

110 
Osmotic relations of blood, 88 

tension, estimation of, 61 
Osteomalacia, 377 

chemistry of, 377 

eosinophiles in, 165, 378 
Osteomyelitis, 321, 324 
Osteosarcoma, 427 
Oxyhemoglobin, chemistry of, 72 
Oxyuris, 206, 473 



INDEX. 



493 



PANARITIUM, 324 
Parasites, intestinal, 473 
eosinophiles with, 165 
in pernicious anemia, 206 
Paratyphoid fever, 307 

baciUi, 314 
Paresis, 384 
Peptone, in leukemia, 248 

occurrence in blood, 77 
Pericarditis, 330 
Peritonitis, 330 

Pernicious anemia, changes in blood, 216 
chemistry, 216 
Hb, 217' 
leucocytes. 221 
red ceils, 218 
lesions in marrow, 212 
''mycroc3i:ic," 355, 213 
pathogenesis, 215 
progressive, 191 

etiology of, general, 204 

special, 206 
historical, 202 
scope of term, 205 
relation to pseudoleukemia, 

259 
resume of chief facts, 222 
transformation into leukemia, 
231, 484 
serumtherapy in, 362, 484 
Perspiration, leucocj^tosis from, 148 
Phagocytosis in malaria, 463 

relation to immunity, 138 
Phthisis, leucocytosis in,^ 346 
Plague, 334 
Plethora, 17, 106 
Pleurisy, 330 
Pneumonia, 282 

blood of, bacteria in, 289, 485 
degeneration of leucocytes in, 288 
eosinophilia in, 288 
glycogen in, 288 
hypoleucocytosis in, 286 
lymphocytes, large, in, 287 

peculiar in, 287 
myelocytes in, 288 
toxicity of serum in, 283 
Poikilocytosis, 100 
Poisoning by antifebrin, 366 
by antipyrin, 366 
by arseniuretted hydrogen, 363 
by carbonic oxide, 366 
by chromic acid, 365 
by guaiacol, 364 
by hydrocyanic acid, 366 
illuminating gas, polycythemia of, 

109, 366 ' ^ ' ^ 

by lead, 113 
by nitrites, 365 
by nitrobenzol, 365 
by phosphorus, polycythemia of, 

109 
by potassium chlorate, 363 
by pyrogallol, 366 
by toadstools, 364 
Polychromasia, 101, 483 



Potycythemia, 106 

after cold baths, 109 

of diarrheal diseases, 109 

of endocarditis, venous stasis, etc., 
109, 411 

of high altitudes, 107 

of illuminating gas poisoning, 109, 
366 

in jaundice, 391 

of newborn infants, 107 

of phosphorus poisoning, 109 
Potassium chlorate poisoning, 364 
Precipitin test, 24 
Pregnane}^, leucocytosis of, 148 

leukemia after, 231 

pernicious anemia after, 207 

red cells in, 106 
Protozoa, in leukemia, 233 

in measles, 296, 300 

in variola, 296 
Pseudoleukema, 254 

acute, 258 

anatomical lesions of, 255 

changes in blood of, 262 

diagnosis of, 264 

histor}^, 254 

infectious origin of, 260 

lymphosarcoma in, 256 

relation of, to leukemia, 258 
to pernicious anemia, 259 
to tuberculosis, 259 

skin in, 255 

spleen in, 257 
Pseudolymphocytes, 125 
Psychical emotions, effect on quality of 

blood, 19 
Purges, effect of, on blood, 403 
Purpura hemorrhagica, 260, 353 
bacteria in, 354 
non-infectious, idiopathic, 213, 
355 
Pyemia, 321 
Pyrogallol poisoning, 366 



QUALITY of blood, effect of nervous 
influences on, 18 
Quantity of blood, 31 



RABIES, 333 
Rachitis, 378 

as cause of leukemia, 231 
chemistry of, 380 
eosinophilia in, 380 
hyperplasia of spleen in, 380 
lymphocytosis in, 380 
Receptors, 142 

Red cells, chemical composition, 71 
development of, 175 
fetal, 101 

granular degeneration, 102. 365, 483 
influence of therapeutic measures 
^ upon, 111 
morphology and physiology, 96 
numbers of, 104 



494 



INDEX. 



Red cells, pathological changes in, 
100 

size of, 97 

staining reactions, 96 
Reduced Hb, chemistry of, 72 
''Reizimgsformen," Turk's, 244, 288 
Relapsing fever, 466 

serum diagnosis in, 468 
Resistance of red cells in fever, 278 
Respiration, effects on blood, 407 
Rheumatism, 327 

bacteria in, 328 

eosinophiles in, 164, 328 



SALT solution, infusion of, 364 
Sarcoma, 427 

eosinophilia in, 428 
lymphocytosis in, 427 
of spleen, 264 
Scarlet fever, 298 

eosinophiles in, 164, 299 
bacteria in, 300 
Schistocytosis, 221 
Scurv}^, 357 

bacteria in, 358 
Septicemia, 321 

in leukemia, 246 
Serum, albumins of, 75 
chemistry of, 75 
diagnosis of blood, 24 
of leprosv, 350 
of Malta fever, 334 
of plague, 334 
in relapsing fever, 468 
of typhoid fever, 311 
globulicidal action of, 76 
infusion of, 364 
inorganic principles of, 75 
specific gravity of, 76 
Serumtherapv in anemia, 362, 484 
in diphtheria, 292 
by hemolysin, 362, 484 
in typhoid fever, 307 
in variola, 297 
Sex, influence on numbers of red cells, 

105 
Skin diseases, eosinophiles in, 163 

lesions in pseudoleukemia, 255 
Sleeping-sickness, 485 
Smears of blood, method of preparing, 

53 
Snake poison, 363 
Specific gravity, in carcinoma, 426 
estimation of, 57 

Hammerschlag's method, 

57 
Schmaltz' s method, 58 
general variations of, 84 
in leukemia, 247 
of serum, 76 
Spectra of blood pigments, 29 
Spectrophotometer, Glan's, 376 
Spermin in leukemia, 246 
Spindle cells, 186 
Spirillum of Obermeier, 466 



Spleen, aspiration of, in tvphoid fever> 
306 
epitheliome primitive of, 264 
extirpation of, in leukemia, 275 

in malaria, 275 
hyperplasia of, in rachitis, 380 
sarcoma of, 264 
svphilis of, 264 
Splenectomy, 273 
in animals, 273 
in man, 274 
Splenic anemia, 264 
Splenocyte, 126, 184 
Spotted fever of Montana, 481 
Staining methods, 55 

dahlia, for mast-cells, 57 
eosinophiles, methvlene blue, 

55 
Jenner's, 56 
triacid mixture, 56 
Nocht's, 434 
Stippling of red cells, 450 
Stomach, carcinoma of, 209, 399, 425 
digestion leucocytosis, 146, 401 
dilatation of, 396 
diseases of, 395 
ulcer of, 398 
Stomatitis, a cause of leukemia, 231 
Suppuration, 326 
Surgical procedures, effects on blood, 

110 
Surra, 480 
Syphilis, 339 

a cause of leukemia, 231 
congenital, 342 

hmiphocytosis in, 171, 342 
myelocytes in, 343 
eosinophiles in, 165 
in pernicious anemia, 207 
of spleen, 264 



TECHNICS, 23 
in malaria, 431 
Tenia, 473 

Tests for blood, qualitative, 23 
guaiacum, 24 
serum, 24 
spectroscopic, 28 
Teichmann's hemin, 24 
Tetanus, 333 
Tetany, 387 

Thoma's hematocvtometer, 35 
Thj^roid chlorosis,' 387 

therapy in myxedema, 381 
Toadstools, poisoning bv, 364 
Tonsillitis, 329 

Toxicity of serum, in pneumonia, 283 
Toxins,^ 143 

Transfusion, effects of, 117, 364 
Trichinosis, 470 
Trj'-panosomiasis, 480 

in sleeping-sickness, 485 
Tuberculin, 171, 246 
Tuberculosis, 343 
bacteria in, 348 



INDEX. 



495 



Tuberculosis of bones, 348 
chemistry of. 348 
meningitis. 347 

relation to pseudoleukemia, 259 
Tumors, eosinophiles in blood, 163, 425 

42S 
Typhoid fever. 302, 

aspiration of spleen in, 306 

bacteria in, 306 

bilious, 468 _ 

a cause of pernicious anemia, 

208 
cold baths in, 304 
lymphocytosis in, 305 
serum diagnosis of, 311 
T^-phus fever, 332^ 
Tvrosin in leukemia, 248 



XyREA, occurrence and estimation of, 
J 80,417 
Uremia, 417 

alkalescence in, 418 
chemistry of, 417 
Uric acid, in blood of gout, 326 
in leukemia, 248 
occurrence and estimation of, 80 
"thread test," 377 



VACCINIA, 297 
blood in, in children, 297 
Varicella, 297 
Variola, 294 

protozoa in, 296 
Varioloid, 294 

Vermiculus, of malaria, 452 
^'olume of red cells and plasma, 31 
of blood, total, 31 

WANDERING cells, primarv, 180 
■ Werlhoff's disease, 353 
Whole blood, chemistry of, 77 

quantitative estimation of 
albumins of, 77 
Whooping-cough, 329 
Widal's test, 311 



VANTHIN bodies in leukemia, 248 
XTELLOW fever, 331 
yAPPERT chamber, 38 



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